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Jian B, Zhang H, Fan L, Li Y, Wu N, Wang N, Li L, Li X, Ge P, Niu Y, Liu J. RAD51 expression and prognostic impact in patients with stomach adenocarcinoma. PeerJ 2025; 13:e19179. [PMID: 40231067 PMCID: PMC11995892 DOI: 10.7717/peerj.19179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 02/25/2025] [Indexed: 04/16/2025] Open
Abstract
Background Stomach adenocarcinoma (STAD) is the most common gastrointestinal cancer. A clear diagnosis and molecular targeted therapy have important implications for prolonging survival of patients. RAD51 is the central catalyst of homologous recombination that plays important role in maintaining genomic integrity. However, the clinical significance of RAD51 expression in STAD patients remains unclear. This study aimed to assess the association of RAD51 expression with clinicopathological characteristics and patient outcomes. Methods In this study, RAD51 mRNA expression in STAD patients was assessed using the UALCAN and GEPIA databases. The diagnostic value of RAD51 was evaluated by analyzing the ROC curve (data from the The Cancer Genome Atlas (TCGA) database). The protein expression level of RAD51 in STAD patients and its relationship with clinicopathological characteristics and prognosis were evaluated by immunohistochemistry. Co-expression analysis of RAD51 in STAD was performed by Coexpedia and Gene Expression Profiling Interactive Analysis (GEPIA) databases. The associations of RAD51 and its co-expression genes with immune infiltrates were analyzed in TIMER database. Results Our bioinformatic analysis revealed that RAD51 demonstrates elevated expression in STAD. The ROC curve analysis yielded an AUC value of 0.9366 (95% CI [0.9075-0.9658]), confirming its potential as a biomarker for STAD. Immunohistochemical assessments validated the up-regulation of RAD51 in STAD, highlighting its significant correlation with TNM stage and T stage, but not with age, sex, grade, N stage, M stage, or P53 expression. Patients exhibiting high RAD51 expression exhibited significantly reduced overall survival. Multivariate analysis identified RAD51 expression may serve as an independent prognostic biomarker of poor prognosis in patients with STAD. Additionally, our bioinformatic analysis identified eight RAD51 co-expression genes (AURKA, CKS1B, NUSAP1, PFDN4, CCNE1, CDCA4, KIF4A, and MCM10) in STAD. Moreover, we discovered that RAD51 and its main co-expressed genes were significantly negatively associated with most or all immune cell infiltration. Conclusions RAD51 overexpression was related to disease progression and poor prognosis, as well as infiltration of immune cells in gastric cancer.
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Affiliation(s)
- Baiyu Jian
- Qiqihar Medical University, Qiqihar, China
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Hao Zhang
- Qiqihar Medical University, Qiqihar, China
| | - Li Fan
- Qiqihar Medical University, Qiqihar, China
| | - Yang Li
- Qiqihar Medical University, Qiqihar, China
| | - Nan Wu
- Qiqihar Medical University, Qiqihar, China
| | | | - Lingmin Li
- Qiqihar Medical University, Qiqihar, China
| | - Xueyan Li
- Qiqihar Medical University, Qiqihar, China
| | - Pengling Ge
- Heilongjiang University of Chinese Medicine, Harbin, China
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Jia Y, Liu M, Liu H, Liang W, Zhu Q, Wang C, Chen Y, Gao Y, Liu Z, Cheng X. DSN1 may predict poor prognosis of lower-grade glioma patients and be a potential target for immunotherapy. Cancer Biol Ther 2024; 25:2425134. [PMID: 39555702 PMCID: PMC11581156 DOI: 10.1080/15384047.2024.2425134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 07/11/2023] [Accepted: 10/30/2024] [Indexed: 11/19/2024] Open
Abstract
DSN1 has been previously found to be positively correlated with various cancers. However, the effect of DSN1 or its methylation on the prognosis, molecular characteristics, and immune cell infiltration of low-grade glioma (LGG) has not yet been studied. We obtained 1046 LGG samples from the The Cancer Genome Atlas, The Chinese Glioma Genome Atlas (CGGA) microarray, and CGGA RNA-Seq databases. Bioinformatic methods (gene set enrichment analysis (GSEA), chi-square test, multivariate), and laboratory validation were used to investigate DSN1 in LGG. The expression levels of DSN1 mRNA and protein in LGG were substantially higher than those in normal brain tissue, and their expression was negatively regulated by methylation. The survival time of patients with low expression of DSN1 and cg12601032 hypermethylation was considerably prolonged. DSN1 was a risk factor, and of good diagnostic and prognostic value for LGG. Importantly, the expression of DSN1 is related to many types of tumor-infiltrating immune cells and has a positive correlation with PDL1. DSN1 promoted the activation of multiple cancer-related pathways, such as the cell cycle. Additionally, knockdown of DSN1 substantially inhibited the proliferation and invasion of LGG cells. To the best of our knowledge, this study is the first comprehensive analysis of the mechanism of DSN1 leading to poor prognosis of LGG, which provides a new perspective for revealing the pathogenesis of LGG. DSN1 or its methylation has diagnostic value for the prognosis of glioma, and may become a new biological target of anti-tumor immunotherapy.
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Affiliation(s)
- Yulong Jia
- Department of Neurosurgery, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
| | - Meiling Liu
- School of Clinical Medicine, Sanquan College of Xinxiang Medical University, Xinxiang, Henan, China
| | - Han Liu
- Department of Clinical Medicine, Medical College of Jinzhou Medical University. Taihe District, Jinzhou, Liaoning Province, China
| | - Wenjia Liang
- Henan Provincial People’s Hospital, People’s Hospital of Henan University, Zhengzhou, Henan Province, China
| | - Qingyun Zhu
- Henan Provincial People’s Hospital, People’s Hospital of Henan University, Zhengzhou, Henan Province, China
| | - Chao Wang
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, P. R. China
| | - Yake Chen
- School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, China
| | - Yanzheng Gao
- Department of Surgery of Spine and Spinal Cord, Henan Provincial People’s Hospital, Henan Province Intelligent orthopedic technology innovation and transformation International Joint Laboratory, Henan Key Laboratory for intelligent precision orthopedics, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, Henan, China
| | - Zhendong Liu
- Department of Surgery of Spine and Spinal Cord, Henan Provincial People’s Hospital, Henan Province Intelligent orthopedic technology innovation and transformation International Joint Laboratory, Henan Key Laboratory for intelligent precision orthopedics, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, Henan, China
| | - Xingbo Cheng
- Department of Surgery of Spine and Spinal Cord, Henan Provincial People’s Hospital, Henan Province Intelligent orthopedic technology innovation and transformation International Joint Laboratory, Henan Key Laboratory for intelligent precision orthopedics, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, Henan, China
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Shafiq MO, Cakir MO, Bilge U, Pasha Y, Ashrafi GH. Transcriptomic Analysis of HPV-Positive Oesophageal Tissue Reveals Upregulation of Genes Linked to Cell Cycle and DNA Replication. Int J Mol Sci 2024; 26:56. [PMID: 39795915 PMCID: PMC11720088 DOI: 10.3390/ijms26010056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 12/17/2024] [Accepted: 12/21/2024] [Indexed: 01/13/2025] Open
Abstract
Human papillomavirus (HPV) is a prevalent sexually transmitted infection, implicated in various cancers, yet its influence in non-cancerous oesophageal tissue remains unclear. This study aims to investigate the gene expression changes associated with high-risk HPV (HR-HPV) in non-cancerous oesophageal tissue to elucidate potential early oncogenic mechanisms. Using RNA sequencing, we compared transcriptomic profiles of HPV-positive and HPV-negative non-cancerous oesophageal tissues. Differential gene expression analysis revealed significant upregulation of cell cycle and DNA replication pathways in HPV-positive samples, specifically involving key genes such as CCNA2, DSN1, and MCM10, which are known to regulate cellular proliferation and genomic stability. Additionally, kinase and transcription factor enrichment analyses highlighted HR-HPV-associated regulatory molecules, including E2F4 and CSNK2A1, suggesting HPV's role in modulating host cell cycle control. These findings support the hypothesis that HPV infection may initiate cellular alterations in oesophageal tissue, potentially predisposing it to malignancy. This study contributes to understanding HPV's impact in non-cancerous tissues and identifies possible biomarkers for early HPV-related cellular changes, offering insights into HPV-driven cancer development beyond traditionally associated sites.
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Affiliation(s)
- Muhammad Osama Shafiq
- School of Life Sciences, Pharmacy and Chemistry, Kingston University London, London KT1 2EE, UK
| | - Muharrem Okan Cakir
- School of Life Sciences, Pharmacy and Chemistry, Kingston University London, London KT1 2EE, UK
| | - Ugur Bilge
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Akdeniz University, Antalya 07050, Turkey
| | - Yasmin Pasha
- Department of Gastroenterology, Kingston Hospital, Kingston Upon Thames, London KT2 7QB, UK
| | - G. Hossein Ashrafi
- School of Life Sciences, Pharmacy and Chemistry, Kingston University London, London KT1 2EE, UK
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Gu Y, Li J, Guan H, Sun C. Prognostic and immunological values of SKA3 for overall survival in lung adenocarcinoma and its RNA binding protein involved mechanisms. J Chemother 2024; 36:566-579. [PMID: 38146901 DOI: 10.1080/1120009x.2023.2298153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 11/18/2023] [Accepted: 12/15/2023] [Indexed: 12/27/2023]
Abstract
This article aimed to investigate the correlations among SKA3 expression and prognosis, clinical relevance, tumor immunity, and RNA-binding protein (RBP)-involved mechanisms for overall survival (OS) in lung adenocarcinoma (LUAD). To explore the SKA3 expression level in LUAD by analyzing the genomic data as well as related clinical characteristics from the database of TCGA. Nomogram and gene set enrichment analysis (GSEA) were applied, respectively, to evaluate the performance of SKA3 in LUAD. Correlations between SKA3 and immunity and RBP-involved mechanisms were also performed. SKA3 had a higher expression level in LUAD samples than in adjacent normal lung samples, with shorter survival times in the high-SKA3-expressed LUAD subgroup (P < 0.05). qRT-PCR results remained consistent (P < 0.05). Uni-/multivariate Cox analyses revealed that SKA3 could have independent prognostic ability for LUAD (both P < 0.05). The nomogram model constructed with clinical pathological parameters and SKA3 expression levels predicted OS rates for LUAD and GSEA revealed SKA3-related pathways. In aspects of tumor immunity, SKA3 was significantly involved with tumor neoantigen burden, tumor mutational burden, immune cell pathways, and immune checkpoint inhibitor (ICI) molecules (all P < 0.05). The CellMiner database also found significant correlations between SKA3 and the antitumor drug sensitivity of chemotherapy, fenretinide, and PX-316. Besides, a total of nine LncRNA/RBP/SKA3 networks were revealed in LUAD for their RBP-involved mechanisms. SKA3 could serve as a potential biomarker for OS prognosis and immunotherapy in LUAD. LncRNA/RBP/SKA3 networks were identified in LUAD for their RBP-involved mechanisms, paving the way for further experimental verifications.
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Affiliation(s)
- Yinfeng Gu
- Department of Thoracic Surgery, Jianhu People's Hospital, Yancheng, Jiangsu, China
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Jinjin Li
- Department of Thoracic Surgery, Jianhu People's Hospital, Yancheng, Jiangsu, China
| | - Hongjun Guan
- Department of Thoracic Surgery, Jianhu People's Hospital, Yancheng, Jiangsu, China
| | - Changpeng Sun
- Department of Thoracic Surgery, Jianhu People's Hospital, Yancheng, Jiangsu, China
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Polverino F, Mastrangelo A, Guarguaglini G. Contribution of AurkA/TPX2 Overexpression to Chromosomal Imbalances and Cancer. Cells 2024; 13:1397. [PMID: 39195284 PMCID: PMC11353082 DOI: 10.3390/cells13161397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/14/2024] [Accepted: 08/15/2024] [Indexed: 08/29/2024] Open
Abstract
The AurkA serine/threonine kinase is a key regulator of cell division controlling mitotic entry, centrosome maturation, and chromosome segregation. The microtubule-associated protein TPX2 controls spindle assembly and is the main AurkA regulator, contributing to AurkA activation, localisation, and stabilisation. Since their identification, AurkA and TPX2 have been described as being overexpressed in cancer, with a significant correlation with highly proliferative and aneuploid tumours. Despite the frequent occurrence of AurkA/TPX2 co-overexpression in cancer, the investigation of their involvement in tumorigenesis and cancer therapy resistance mostly arises from studies focusing only on one at the time. Here, we review the existing literature and discuss the mitotic phenotypes described under conditions of AurkA, TPX2, or AurkA/TPX2 overexpression, to build a picture that may help clarify their oncogenic potential through the induction of chromosome instability. We highlight the relevance of the AurkA/TPX2 complex as an oncogenic unit, based on which we discuss recent strategies under development that aim at disrupting the complex as a promising therapeutic perspective.
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Affiliation(s)
| | | | - Giulia Guarguaglini
- Institute of Molecular Biology and Pathology, National Research Council of Italy, c/o Sapienza University of Rome, Via degli Apuli 4, 00185 Rome, Italy; (F.P.); (A.M.)
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Feng D, Wang J, Xiao Y, Wu R, Li D, Tuo Z, Yu Q, Ye L, MIYAMOTO A, Yoo KH, Wei W, Ye X, Zhang C, Han P. SKA3 targeted therapies in cancer precision surgery: bridging bench discoveries to clinical applications - review article. Int J Surg 2024; 110:2323-2337. [PMID: 38241327 PMCID: PMC11020031 DOI: 10.1097/js9.0000000000001123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 01/09/2024] [Indexed: 01/21/2024]
Abstract
Spindle and kinetochore-associated complex subunit 3 (SKA3) is a microtubule-binding subcomplex of the outer kinetochore, which plays a vital role in proper chromosomal segregation and cell division. Recently, SKA3 have been demonstrated its oncogenic role of tumorigenesis and development in cancers. In this review, the authors comprehensively deciphered SKA3 in human cancer from various aspects, including bibliometrics, pan-cancer analysis, and narrative summary. The authors also provided the top 10 predicted drugs targeting SKA3. The authors proposed that SKA3 was a potential target and brought new therapeutic opportunities for cancer patients.
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Affiliation(s)
- Dechao Feng
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou
| | - Jie Wang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Yuhan Xiao
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Ruicheng Wu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Dengxiong Li
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Zhouting Tuo
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei
| | - Qingxin Yu
- Department of Pathology, Ningbo Clinical Pathology Diagnosis Center, Ningbo City, Zhejiang Province
| | - Luxia Ye
- Department of Public Research Platform, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, People’s Republic of China
| | - Akira MIYAMOTO
- Department of Rehabilitation, West Kyushu University, Japan
| | - Koo Han Yoo
- Department of Urology, Kyung Hee University, South Korea
| | - Wuran Wei
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Xing Ye
- Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Chi Zhang
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou
| | - Ping Han
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu
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7
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Liang G, Duan C, He J, Shi L. Spindle and kinetochore-related complex subunit 3 has a protumour function in osteosarcoma by activating the Notch pathway. Toxicol Appl Pharmacol 2024; 483:116826. [PMID: 38228236 DOI: 10.1016/j.taap.2024.116826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 12/27/2023] [Accepted: 01/12/2024] [Indexed: 01/18/2024]
Abstract
Increasing expression of spindle and kinetochore-related complex subunit 3 (SKA3) is related to the progression of multiple malignancies. However, the role of SKA3 in osteosarcoma remains unexplored. The present study aimed to investigate the relevance of SKA3 in osteosarcoma. Preliminarily, SKA3 expression in osteosarcoma was assessed through The Cancer Genome Atlas (TCGA) analysis, which revealed high levels of SKA3 transcripts in osteosarcoma tissues. Subsequent examination of clinical tissues confirmed the abundant expression of SKA3 in osteosarcoma. Downregulation of SKA3 expression in osteosarcoma cell lines resulted in repressive effects on cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT), while upregulation of SKA3 expression had the opposite effect. Gene set enrichment analysis (GSEA) revealed that the Notch pathway is enriched in SKA3 high groups based on different expressed genes from the TCGA data. Further investigation showed that the levels of Notch1, Notch1 intracellular domain (NICD1), hairy and enhancer of split 1 (HES1), and hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1) were downregulated in SKA3-silenced osteosarcoma cells, and upregulated in SKA3-overexpressed osteosarcoma cells. Activation of the Notch pathway by increasing NICD1 expression reversed the antitumour effects induced by SKA3 silencing, while deactivation of the Notch pathway diminished the protumour effects induced by SKA3 overexpression. Moreover, SKA3-silenced osteosarcoma cells exhibited a reduced capacity for xenograft formation in nude mice. In conclusion, SKA3 plays a cancer-enhancing role in osteosarcoma through its effect on the Notch pathway. Reducing the expression of SKA3 could be a potential therapeutic approach for treating osteosarcoma.
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Affiliation(s)
- Gaofeng Liang
- Department of Orthopaedics, 521 Hospital of Norinco Group, Xi'an 710061, China
| | - Chaopeng Duan
- Department of Orthopaedics, 521 Hospital of Norinco Group, Xi'an 710061, China
| | - June He
- Department of Orthopaedics, 521 Hospital of Norinco Group, Xi'an 710061, China
| | - Liang Shi
- Department of Orthopedics, Shaanxi Provincial People's Hospital, Xi'an 710068, China.
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Li C, Cao S, Guo M, Guo A, Sun X. Identification of potential key genes for colorectal cancer based on bioinformatics analysis. Medicine (Baltimore) 2023; 102:e36615. [PMID: 38134110 PMCID: PMC10735105 DOI: 10.1097/md.0000000000036615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 11/21/2023] [Indexed: 12/24/2023] Open
Abstract
This study aimed to explore key genes as potential biomarkers for colorectal cancer (CRC) diagnosis and prognosis in order to improve their clinical utility. To identify and screen candidate genes involved in CRC carcinogenesis and disease progression, we downloaded the microarray datasets GSE143939, GSE196006, and GSE200427 from the GEO database and applied the GEO2R tool to obtain differentially expressed genes (DEGs) between colorectal cancer tissue samples and normal tissue samples. Differentially expressed genes were analyzed using the DAVID online database for gene ontology and Kyoto encyclopedia of genes and genomes pathway enrichment analyses. Protein-protein interaction network was constructed and related module analysis was performed using STRING and Cytoscape. In total, 241 DEGs were identified, including 127 downregulated and 114 upregulated genes. DEGs enriched functions and pathways included cellular response to chemical stimulus, extracellular region, carbonate dehydratase activity, cell division, spindle, and cell division. The abundant functions and pathways of DEGs included cellular response to chemical stimulus, extracellular region, carbonate dehydratase activity, cell division, spindle, cell adhesion molecule binding, Aldosterone-regulated sodium reabsorption, and Cell cycle-related processes. Fifteen key genes were identified, and bioprocess analyses showed that these genes were mainly enriched in cell cycle, cell division, mitotic spindle, and tubulin binding processes. It was found that CDK1, CEP55, MKI67, and TOP2A may be involved in CRC cancer invasion and recurrence. The pivotal genes identified in this study contribute to our understanding of the molecular and pathogenic mechanisms of CRC carcinogenesis and progression, and provide possible biomarkers for the diagnosis and treatment of CRC.
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Affiliation(s)
- Chongyang Li
- Second Clinical Medical College, Binzhou Medical University, Yantai, China
- Jinan Fourth People’s Hospital, Jinan, China
| | | | - Mingxiao Guo
- Department of General Surgery Center, Linyi People’s Hospital, Linyi, China
| | - Aihong Guo
- Jinan Fourth People’s Hospital, Jinan, China
| | - Xuedi Sun
- Jinan Fourth People’s Hospital, Jinan, China
- Jinzhou Medical University, Jinzhou, China
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Terasaki M, Tsuruoka K, Tanaka T, Maeda H, Shibata M, Miyashita K, Kanemitsu Y, Sekine S, Takahashi M, Yagishita S, Hamada A. Fucoxanthin Inhibits Development of Sigmoid Colorectal Cancer in a PDX Model With Alterations of Growth, Adhesion, and Cell Cycle Signals. Cancer Genomics Proteomics 2023; 20:686-705. [PMID: 38035706 PMCID: PMC10687734 DOI: 10.21873/cgp.20416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 10/21/2023] [Accepted: 10/23/2023] [Indexed: 12/02/2023] Open
Abstract
BACKGROUND/AIM Fucoxanthin (Fx), a dietary marine xanthophyll, exerts potent anticancer effects in various colorectal cancer (CRC) animal models. However, therapeutic effects of Fx in human cancer tissues remain unclear. A patient-derived xenograft (PDX) mouse model transplanted with cancer tissues from patients is widely accepted as the best preclinical model for evaluating the anticancer potential of drug candidates. MATERIALS AND METHODS Herein, we investigated the anticancer effects of Fx in PDX mice transplanted with cancer tissues derived from a patient with CRC (CRC-PDX) using LC-MS/MS- and western blot-based proteome analysis. RESULTS The tumor in the patient with CRC was a primary adenocarcinoma (T3N0M0, stage II) showing mutations of certain genes that were tumor protein p53 (TP53), AT-rich interaction domain 1A (ARID1A), neuroblastoma RAS viral oncogene homolog (NRAS), and PMS1 homolog 2 (PMS2). Administration of Fx significantly suppressed the tumor growth (0.6-fold) and tended to induce differentiation in CRC-PDX mice. Fx up-regulated glycanated-decorin (Gc-DCN) expression, and down-regulated Kinetochore-associated protein DSN1 homolog (DSN1), phospho(p) focal adhesion kinase (pFAK)(Tyr397), pPaxillin(Tyr31), and c-MYC involved in growth, adhesion, and/or cell cycle, in the tumors of CRC-PDX mice than in control mice. Alterations in the five proteins were consistent with those in human CRC HT-29 and HCT116 cells treated with fucoxanthinol (FxOH, a major metabolite of Fx). CONCLUSION Fx suppresses development of human-like CRC tissues, especially through growth, adhesion, and cell cycle signals.
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Affiliation(s)
- Masaru Terasaki
- School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Hokkaido, Japan;
- Advanced Research Promotion Center, Health Sciences University of Hokkaido, Hokkaido, Japan
| | - Kirara Tsuruoka
- School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Hokkaido, Japan
| | - Takuji Tanaka
- Department of Diagnostic Pathology and Research Center of Diagnostic Pathology, Gifu Municipal Hospital, Gifu, Japan
| | - Hayato Maeda
- Faculty of Agriculture and Life Science, Hirosaki University, Aomori, Japan
| | - Masaki Shibata
- Faculty of Agriculture and Life Science, Hirosaki University, Aomori, Japan
| | | | - Yukihide Kanemitsu
- Colorectal Surgery Division, National Cancer Center Hospital, Tokyo, Japan
| | - Shigeki Sekine
- Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
| | - Mami Takahashi
- Central Animal Division, National Cancer Center, Tokyo, Japan
| | - Shigehiro Yagishita
- Division of Molecular Pharmacology, National Cancer Center Research Institute, Tokyo, Japan
| | - Akinobu Hamada
- Division of Molecular Pharmacology, National Cancer Center Research Institute, Tokyo, Japan
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Yang C, Plum PS, Gockel I, Thieme R. Pan-cancer analysis and in vitro validation of the oncogenic and prognostic roles of AURKA in human cancers. Front Oncol 2023; 13:1186101. [PMID: 37965456 PMCID: PMC10642189 DOI: 10.3389/fonc.2023.1186101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 10/09/2023] [Indexed: 11/16/2023] Open
Abstract
Background Aurora kinase A (AURKA) plays a pivotal role in regulating cell mitosis and tumor progression. However, its prognostic significance across diverse cancer types remains relatively unexplored. Methods We conducted a comprehensive analysis of AURKA expression in various cancers using data from The Cancer Genome Atlas, Genotype-Tissue Expression, and The Human Protein Atlas databases. Our investigation encompassed an exploration of the associations between AURKA expression and clinical characteristics, shedding light on potential functional roles of AURKA. Additionally, we delved into the relationship between AURKA and the tumor microenvironment. To substantiate the role of AURKA, we carried out in vitro experiments in esophageal adenocarcinoma (EAC), prostate cancer (PRAD), and pancreatic cancer (PAAD) cells. Results Our analysis revealed that AURKA is prominently overexpressed in a majority of the cancer types under investigation. Elevated AURKA expression correlated closely with poorer prognosis and advanced tumor stages. AURKA was found to be associated with key pathways involved in the cell cycle and arachidonic acid metabolism. Moreover, AURKA expression exhibited significant correlations with immunoregulatory genes and immune cell profiles. Notably, in vitro experiments demonstrated that silencing AURKA expression resulted in reduced cell viability in EAC, PRAD, and PAAD cells, as well as a decrease in clone formation, cell cycle elongation, diminished cell invasion and reduced spheroid size in EAC cells (OE33 and OE19). Conclusion Our study elucidates the oncogenic role of AURKA and underscores its prognostic value across a spectrum of cancers, including EAC. These findings suggest that AURKA holds promise as a predictive biomarker for EAC and various other tumor types.
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Affiliation(s)
| | | | | | - René Thieme
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
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Zheng LL, Wang YR, Liu ZR, Wang ZH, Tao CC, Xiao YG, Zhang K, Wu AK, Li HY, Wu JX, Xiao T, Rong WQ. High spindle and kinetochore-associated complex subunit-3 expression predicts poor prognosis and correlates with adverse immune infiltration in hepatocellular carcinoma. World J Gastrointest Surg 2023; 15:1600-1614. [PMID: 37701707 PMCID: PMC10494596 DOI: 10.4240/wjgs.v15.i8.1600] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 06/14/2023] [Accepted: 07/17/2023] [Indexed: 08/25/2023] Open
Abstract
BACKGROUND Spindle and kinetochore-associated complex subunit 3 (SKA3) is a malignancy-associated gene that plays a critical role in the regulation of chromosome separation and cell division. However, the molecular mechanism through which SKA3 regulates tumor cell proliferation in hepatocellular carcinoma (HCC) has not been fully elucidated. AIM To investigate the molecular mechanisms underlying the role of SKA3 in HCC. METHODS SKA3 expression, clinicopathological, and survival analyses were performed using multiple public database platforms, and the results were verified by Western blot and immunohistochemistry staining using collected clinical samples. Functional enrichment analyses were performed to evaluate the biological functions and molecular mechanisms of SKA3 in HCC. Furthermore, the Tumor Immune Estimation Resource and single-sample Gene Set Enrichment Analysis (ssGSEA) algorithms were utilized to investigate the abundance of tumor-infiltrating immune cells in HCC. The response to chemotherapeutic drugs was evaluated by the R package "pRRophetic". RESULTS We found that upregulated SKA3 expression was significantly correlated with poor prognosis in patients with HCC. Multivariable Cox regression analysis indicated that SKA3 was an independent risk factor for survival. GSEA revealed that SKA3 expression may facilitate proliferation and migratory processes by regulating the cell cycle and DNA repair. Moreover, patients with high SKA3 expression had significantly decreased ratios of CD8+ T cells, natural killer cells, and dendritic cells. Drug sensitivity analysis showed that the high SKA3 group was more sensitive to sorafenib, sunitinib, paclitaxel, doxorubicin, gemcitabine, and vx-680. CONCLUSION High SKA3 expression led to poor prognosis in patients with HCC by enhancing HCC proliferation and repressing immune cell infiltration surrounding HCC. SKA3 may be used as a biomarker for poor prognosis and as a therapeutic target in HCC.
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Affiliation(s)
- Lin-Lin Zheng
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ya-Ru Wang
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zhen-Rong Liu
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zhi-Hao Wang
- Department of Hepatobiliary Hernia Surgery, Liaocheng Dongcangfu People's Hospital, Liaocheng 252000, Shandong Province, China
| | - Chang-Cheng Tao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yong-Gang Xiao
- The Second Ward of Hepatobiliary Surgery, Qianxinan People's Hospital, Xingyi 562400, Guizhou Province, China
| | - Kai Zhang
- Department of Interventional Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300000, China
| | - An-Ke Wu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Hai-Yang Li
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jian-Xiong Wu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ting Xiao
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wei-Qi Rong
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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12
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Li H, Liu J, Liu W, Zheng L, Chen J. Investigation of potential prognostic biomarkers for colorectal cancer. Arch Med Sci 2023; 21:425-436. [PMID: 40395892 PMCID: PMC12087331 DOI: 10.5114/aoms/167397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 06/03/2023] [Indexed: 05/22/2025] Open
Abstract
Introduction Colorectal cancer (CRC) is the third leading cause of cancer-related death. Since CRC is largely asymptomatic until the alert features develop to an advanced stage, implementation of a screening program is important to reduce cancer morbidity and mortality. Current screening methods have significant limitations. Material and methods CRC-related microarray datasets were collected from the GEO database and differentially expressed genes (DEGs) were identified. Next, Venn analysis, functional enrichment analysis, protein interaction network (PPI) analysis, and survival analysis were performed. Results A total of 5267 and 4233 DEGs were identified in two datasets (GSE20916, GSE33133). The intersection of up-regulated genes in the two datasets was obtained by Venn Analysis as 1058 DEGs. Among the 1058 genes, 992 genes with survival and clinical information in TCGA were screened. Eleven DEGs were identified as potential prognostic markers. Model results show that the time period with the most obvious prognostic effect is 5 years, and the AUC value is the highest. ROC curve results are consistent with the model results of the survival analysis. The survival curve showed that LRRC8A, PCAT6, PLA2G15, SRD5A1, T1GD1 may be oncogenes, and DSN1, ERI1, EIT1, GLMN, MAPKAPK, NOP14 may be tumor suppressor genes. Conclusions This study discovers novel prognostic markers through Cox regression and survival analysis, and provides a theoretical basis for the treatment of CRC.
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Affiliation(s)
- Hui Li
- Department of Abdominal Radiotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, China
| | - Jie Liu
- Department of Abdominal Radiotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, China
| | - WenHui Liu
- Department of Radiation Oncology, Mengchao Hepatobiliary Hospital of Fujian Medical University, China
| | - Liang Zheng
- Department of Abdominal Radiotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, China
| | - JuHui Chen
- Department of Abdominal Radiotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, China
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13
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Khazaei-Poul Y, Mirmotalebisohi SA, Zali H, Molavi Z, Mohammadi-Yeganeh S. Identification of miR-3182 and miR-3143 target genes involved in the cell cycle as a novel approach in TNBC treatment: A systems biology approach. Chem Biol Drug Des 2023; 101:662-677. [PMID: 36310371 DOI: 10.1111/cbdd.14167] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 10/15/2022] [Accepted: 10/24/2022] [Indexed: 02/04/2023]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis, lacking therapeutic targets. miRNAs play crucial roles in TNBC through regulating various mechanisms, including cellular growth and proliferation. This study aims to identify critical target genes of two novel miRNAs (miR-3143 and miR-3182) involved in the cell cycle of TNBC as possible therapeutic targets and investigates their regulatory and therapeutic roles through a systems biology approach and in vitro experiment. Datasets related to the TNBC cell line (MDA-MB-231) were screened and retrieved, and Gene regulatory networks were constructed. Significant regulatory motifs were detected and analyzed using the FANMOD and Cytoscape analyzer, and the clusters and seeds were identified using the MCODE. Functional enrichment analysis was also performed using DAVID and STRING. The most critical genes were determined using the analysis of GRN motifs and PPI clusters. The essential genes involved in the cell cycle were selected and verified using the bc-GenExMiner v4.7. We overexpressed miR-3143 and miR-3182 in the MDA-MB-231 cell line using human umbilical cord mesenchymal stem cell (HUCMSC)-miRNA loaded exosomes, and the expression of the critical target genes was investigated using RT-qPCR. We identified eight critical genes as potential therapeutic targets. Their expression decreased by overexpression of miR-3143 and miR-3182 in RT-qPCR. The identified critical genes have probably significant roles in the pathogenesis of TNBC through the cell cycle. We suggest that the overexpression of miR-3143 and miR-3182 could be a new therapeutic candidate in TNBC and is worth more investigation.
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Affiliation(s)
- Yalda Khazaei-Poul
- Student Research Committee, Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Amir Mirmotalebisohi
- Student Research Committee, Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hakimeh Zali
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Molavi
- Proteomics Research Center, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Samira Mohammadi-Yeganeh
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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14
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Lo CH, Wu DC, Jao SW, Wu CC, Lin CY, Chuang CH, Lin YB, Chen CH, Chen YT, Chen JH, Hsiao KH, Chen YJ, Chen YT, Wang JY, Li LH. Enrichment of Prevotella intermedia in human colorectal cancer and its additive effects with Fusobacterium nucleatum on the malignant transformation of colorectal adenomas. J Biomed Sci 2022; 29:88. [PMID: 36303164 PMCID: PMC9615364 DOI: 10.1186/s12929-022-00869-0] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 10/18/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Owing to the heterogeneity of microbiota among individuals and populations, only Fusobacterium nucleatum and Bacteroides fragilis have been reported to be enriched in colorectal cancer (CRC) in multiple studies. Thus, the discovery of additional bacteria contributing to CRC development in various populations can be expected. We aimed to identify bacteria associated with the progression of colorectal adenoma to carcinoma and determine the contribution of these bacteria to malignant transformation in patients of Han Chinese origin. METHODS Microbiota composition was determined through 16S rRNA V3-V4 amplicon sequencing of autologous adenocarcinomas, adenomatous polyps, and non-neoplastic colon tissue samples (referred to as "tri-part samples") in patients with CRC. Enriched taxa in adenocarcinoma tissues were identified through pairwise comparison. The abundance of candidate bacteria was quantified through genomic quantitative polymerase chain reaction (qPCR) in tissue samples from 116 patients. Associations of candidate bacteria with clinicopathological features and genomic and genetic alterations were evaluated through odds ratio tests. Additionally, the effects of candidate bacteria on CRC cell proliferation, migration, and invasion were evaluated through the co-culture of CRC cells with bacterial cells or with conditioned media from bacteria. RESULTS Prevotella intermedia was overrepresented in adenocarcinomas compared with paired adenomatous polyps. Furthermore, co-abundance of P. intermedia and F. nucleatum was observed in tumor tissues. More notably, the coexistence of these two bacteria in adenocarcinomas was associated with lymph node involvement and distant metastasis. These two bacteria also exerted additive effects on the enhancement of the migration and invasion abilities of CRC cells. Finally, conditioned media from P. intermedia promoted the migration and invasion of CRC cells. CONCLUSION This report is the first to demonstrate that P. intermedia is enriched in colorectal adenocarcinoma tissues and enhances the migration and invasion abilities of CRC cells. Moreover, P. intermedia and F. nucleatum exert additive effects on the malignant transformation of colorectal adenomas into carcinomas. These findings can be used to identify patients at a high risk of malignant transformation of colorectal adenomas or metastasis of CRC, and they can accordingly be provided optimal clinical management.
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Affiliation(s)
- Chia-Hui Lo
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Deng-Chyang Wu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shu-Wen Jao
- Division of Colon and Rectal Surgery, Tri-Service General Hospital, Taipei, Taiwan
| | - Chang-Chieh Wu
- Division of Colon and Rectal Surgery, Tri-Service General Hospital, Taipei, Taiwan
| | - Chung-Yen Lin
- Institute of Information Science, Academia Sinica, Taipei, Taiwan
| | | | - Ya-Bo Lin
- Institute of Information Science, Academia Sinica, Taipei, Taiwan
| | - Chien-Hsiun Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Ying-Ting Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Jiann-Hwa Chen
- Scool of Medicine, Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan
| | - Koung-Hung Hsiao
- Department of Colorectal Surgery, Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan
| | - Ying-Ju Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Yuan-Tsong Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Jaw-Yuan Wang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Pingtung Hospital, Ministry of Health and Welfare, Pingtung, Taiwan.
| | - Ling-Hui Li
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
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15
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Wang C, Liu S, Zhang X, Wang Y, Guan P, Bu F, Wang H, Wang D, Fan Y, Hou S, Qiu Z. SKA3 is a prognostic biomarker and associated with immune infiltration in bladder cancer. Hereditas 2022; 159:20. [PMID: 35546682 PMCID: PMC9092687 DOI: 10.1186/s41065-022-00234-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 04/22/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Spindle and kinetochore‑associated complex subunit 3 (SKA3) has recently been considered a key regulator of carcinogenesis. However, the connection between SKA3 and immune cell infiltration remains unknown. METHODS The current study investigated the expression mode, prognostic effect, and functional role of SKA3 in different tumors, particularly bladder cancer using numerous databases, comprising TIMER, GEPIA, HPA, UALCAN, PrognoScan, and Kaplan-Meier Plotter. Differentially expressed gene and enrichment analyses were implemented on SKA3 using R packages "edgR" and "clusterProfiler". Immunohistochemistry was further used to validate the expression of SKA3 gene in bladder cancer. Following that, the relevance of SKA3 expression to immune infiltration level in bladder cancer was evaluated using TIMER. RESULTS Overall, the level of SKA3 expression in tumor tissue significantly increased than in normal tissue. In bladder cancer and other tumors, patients with high SKA3 expression levels had worse overall survival (OS) (p = 0.016), disease-specific survival (DSS) (p = 0.00004), and disease-free survival (DFS) (p = 0.032). Additionally, the major molecular functions for SKA3 included nuclear division, mitotic nuclear division, mitotic sister chromatid segregation, humoral immune response, and cell chemotaxis. Additionally, SKA3 expression was found to be positively associated with enhanced M2 macrophage and T helper (Th) 2 cell infiltration in bladder cancer. CONCLUSIONS Our study implies that SKA3 contributes to M2 macrophage and Th2 cell polarization by acting as an oncogene in bladder cancer. SKA3 might be a novel biomarker for evaluating prognosis and immune infiltration in bladder cancer.
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Affiliation(s)
- Chenyang Wang
- Department of Urology, Qingdao Municipal Hospital, Qingdao University, 266071, Qingdao, Shandong, China
| | - Shasha Liu
- Department of Urology, Qingdao Municipal Hospital, Qingdao University, 266071, Qingdao, Shandong, China
| | - Xinhong Zhang
- Department of Urology, Qingdao Municipal Hospital, Qingdao University, 266071, Qingdao, Shandong, China
| | - Yan Wang
- Department of Anesthesiology and Surgery, Qingdao Municipal Hospital, Qingdao University, 266071, Qingdao, Shandong, China
| | - Peng Guan
- Department of Urology, Qingdao Municipal Hospital, Qingdao University, 266071, Qingdao, Shandong, China
| | - Fanyou Bu
- Department of Traditional Chinese Medicine, Qingdao Municipal Hospital, Qingdao University, 266071, Qingdao, Shandong, China
| | - Hao Wang
- Department of Oncology, Qingdao Municipal Hospital, Qingdao University, 266071, Qingdao, Shandong, China
| | - Dawen Wang
- Department of Urology, Qingdao Municipal Hospital, Qingdao University, 266071, Qingdao, Shandong, China
| | - Yi Fan
- Department of Urology, Qingdao Municipal Hospital, Qingdao University, 266071, Qingdao, Shandong, China
| | - Sichuan Hou
- Department of Urology, Qingdao Municipal Hospital, Qingdao University, 266071, Qingdao, Shandong, China
| | - Zhilei Qiu
- Department of Urology, Qingdao Municipal Hospital, Qingdao University, 266071, Qingdao, Shandong, China.
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16
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Wang X, Lu X, Wang P, Chen Q, Xiong L, Tang M, Hong C, Lin X, Shi K, Liang L, Lin J. SRSF9 promotes colorectal cancer progression via stabilizing DSN1 mRNA in an m6A-related manner. J Transl Med 2022; 20:198. [PMID: 35509101 PMCID: PMC9066907 DOI: 10.1186/s12967-022-03399-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 04/19/2022] [Indexed: 12/13/2022] Open
Abstract
Background Serine/arginine-rich splicing factor 9 (SRSF9) is a classical RNA-binding protein that is essential for regulating gene expression programs through its interaction with target RNA. Whether SRSF9 plays an essential role in colorectal cancer (CRC) progression and can serve as a therapeutic target is largely unknown. Here, we highlight new findings on the role of SRSF9 in CRC progression and elucidate the underlying mechanism. Methods CRC cell lines and clinical tissue samples were used. qRT-PCR, Western blotting, immunohistochemistry (IHC), gain- and loss-of-function assays, animal xenograft model studies, bioinformatic analysis, methylated single-stranded RNA affinity assays, gene-specific m6A quantitative qRT-PCR, dual-luciferase reporter assays and RNA stability assays were performed in this study. Results The expression level of SRSF9 was higher in CRC cell lines than that in an immortal human intestinal epithelial cell line. Overexpression of SRSF9 was positively associated with lymph node metastasis and Dukes stage. Functionally, SRSF9 promoted cell proliferation, migration and invasion in vitro and xenograft growth. The results of bioinformatic analysis indicated that DSN1 was the downstream target of SRSF9. In CRC cells and clinical tissue samples, the expression of SRSF9 was positively associated with the expression of DSN1. Knockdown of DSN1 partially inhibited the SRSF9-induced phenotype in CRC cells. Mechanistically, we further found that SRSF9 is an m6A-binding protein and that m6A modifications were enriched in DSN1 mRNA in CRC cells. Two m6A modification sites (chr20:36773619–36773620 and chr20:36773645–chr20:36773646) in the SRSF9-binding region (chr20:36773597–36773736) of DSN1 mRNA were identified. SRSF9 binds to DSN1 in an m6A motif- and dose-dependent manner. SRSF9 modulates the expression of DSN1 in CRC cells. Such expression regulation was largely impaired upon methyltransferase METTL3 knockdown. Moreover, knockdown of SRSF9 accelerated DSN1 mRNA turnover, while overexpression of SRSF9 stabilized DSN1 mRNA in CRC cells. Such stabilizing was also weakened upon METTL3 knockdown. Conclusion Overexpression of SRSF9 was associated with lymph node metastasis and Dukes stage in CRC. Knockdown of DSN1 eliminated the effects by SRSF9 overexpression in CRC. Our results indicated that SRSF9 functions as an m6A-binding protein (termed “reader”) by enhancing the stability of DSN1 mRNA in m6A-related manner. Our study is the first to report that SRSF9-mediated m6A recognition has a crucial role in CRC progression, and highlights SRSF9 as a potential therapeutic target for CRC management. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03399-3.
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Affiliation(s)
- Xiaoyu Wang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Xiansheng Lu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Ping Wang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Qiaoyu Chen
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Le Xiong
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Minshan Tang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Chang Hong
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Xiaowen Lin
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Kaixi Shi
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Li Liang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Jie Lin
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China. .,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China. .,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, Guangdong, People's Republic of China.
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17
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Lin Y, An J, Zhuo X, Qiu Y, Xie W, Yao W, Yin D, Wu L, Lei D, Li C, Xie Y, Hu A, Li S. Integrative Multi-Omics Analysis of Identified SKA3 as a Candidate Oncogene Correlates with Poor Prognosis and Immune Infiltration in Lung Adenocarcinoma. Int J Gen Med 2022; 15:4635-4647. [PMID: 35535142 PMCID: PMC9078431 DOI: 10.2147/ijgm.s359987] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 04/05/2022] [Indexed: 11/23/2022] Open
Affiliation(s)
- Yuansheng Lin
- Department of Emergency and Critical Care Medicine, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, People’s Republic of China
| | - Jianzhong An
- Department of Emergency and Critical Care Medicine, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, People’s Republic of China
| | - Xingli Zhuo
- Department of Emergency and Critical Care Medicine, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, People’s Republic of China
| | - Yingzhuo Qiu
- Department of Emergency and Critical Care Medicine, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, People’s Republic of China
| | - Wenjing Xie
- Department of Emergency and Critical Care Medicine, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, People’s Republic of China
| | - Wei Yao
- Department of Emergency and Critical Care Medicine, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, People’s Republic of China
| | - Dan Yin
- Department of Emergency and Critical Care Medicine, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, People’s Republic of China
| | - Linpeng Wu
- Department of Emergency and Critical Care Medicine, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, People’s Republic of China
| | - Dian Lei
- Department of Emergency and Critical Care Medicine, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, People’s Republic of China
| | - Chenghui Li
- Department of Emergency and Critical Care Medicine, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, People’s Republic of China
| | - Yuanguang Xie
- Department of Emergency and Critical Care Medicine, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, People’s Republic of China
| | - Ahu Hu
- Department of Emergency and Critical Care Medicine, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, People’s Republic of China
- Correspondence: Ahu Hu; Shengjun Li, Department of emergency and critical care medicine, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, No. 1 Lijiang Road, Suzhou, 215000, People’s Republic of China, Email ;
| | - Shengjun Li
- Department of Emergency and Critical Care Medicine, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, People’s Republic of China
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Zhang C, Zhao S, Tan Y, Pan S, An W, Chen Q, Wang X, Xu H. The SKA3-DUSP2 Axis Promotes Gastric Cancer Tumorigenesis and Epithelial-Mesenchymal Transition by Activating the MAPK/ERK Pathway. Front Pharmacol 2022; 13:777612. [PMID: 35295342 PMCID: PMC8918524 DOI: 10.3389/fphar.2022.777612] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 02/11/2022] [Indexed: 12/24/2022] Open
Abstract
Background: Spindle and kinetochore-related complex subunit 3 (SKA3), a member of the SKA family of proteins, is associated with the progression of multiple cancers. However, the role of SKA3 in gastric cancer has not been studied.Methods: The expression levels of SKA3 and dual-specificity phosphatase 2 (DUSP2) proteins were detected by immunohistochemistry. The effects of SKA3 and DUSP2 on the proliferation, migration, invasion, adhesion, and epithelial-mesenchymal transition of gastric cancer were studied in vitro and in vivo.Results: Immunohistochemical analysis of 164 cases of gastric cancer revealed that high expression of SKA3 was negatively correlated with DUSP2 expression and related to N stage, peritoneal metastasis, and poor prognosis. In vitro studies showed that silencing SKA3 expression inhibited the proliferation, migration, invasion, adhesion and epithelial-mesenchymal transition of gastric cancer. In vivo experiments showed that silencing SKA3 inhibited tumor growth and peritoneal metastasis. Mechanistically, SKA3 negative regulates the tumor suppressor DUSP2 and activates the MAPK/ERK pathway to promote gastric cancer.Conclusion: Our results indicate that the SKA3-DUSP2-ERK1/2 axis is involved in the regulation of gastric cancer progression, and SKA3 is a potential therapeutic target for gastric cancer.
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Affiliation(s)
- Chao Zhang
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Shutao Zhao
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Yuen Tan
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, Shenyang, China
- Key Laboratory of Gastric Cancer Molecular Pathology of Liaoning Province, Shenyang, China
| | - Siwei Pan
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, Shenyang, China
- Key Laboratory of Gastric Cancer Molecular Pathology of Liaoning Province, Shenyang, China
| | - Wen An
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, Shenyang, China
- Key Laboratory of Gastric Cancer Molecular Pathology of Liaoning Province, Shenyang, China
| | - Qingchuan Chen
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, Shenyang, China
- Key Laboratory of Gastric Cancer Molecular Pathology of Liaoning Province, Shenyang, China
| | - Xudong Wang
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, China
- *Correspondence: Xudong Wang, ; Huimian Xu,
| | - Huimian Xu
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, Shenyang, China
- Key Laboratory of Gastric Cancer Molecular Pathology of Liaoning Province, Shenyang, China
- *Correspondence: Xudong Wang, ; Huimian Xu,
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Chen X, Liu C, Zhang Z, Wang M, Guo S, Li T, Sun H, Zhang P. ZNF655 Promotes the Progression of Glioma Through Transcriptional Regulation of AURKA. Front Oncol 2022; 12:770013. [PMID: 35280721 PMCID: PMC8907887 DOI: 10.3389/fonc.2022.770013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 01/10/2022] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVES Glioma has a high degree of malignancy, strong invasiveness, and poor prognosis, which is always a serious threat to human health. Previous studies have reported that C2H2 zinc finger (ZNF) protein is involved in the progression of various cancers. In this study, the clinical significance, biological behavior, and molecule mechanism of ZNF655 in glioma were explored. METHODS The expression of ZNF655 in glioma and its correlation with prognosis were analyzed through public datasets and immunohistochemical (IHC) staining. The shRNA-mediated ZNF655 knockdown was used to explore the effects of ZNF655 alteration on the phenotypes and tumorigenesis of human glioma cell lines. Chromatin immunoprecipitation (ChIP)-qPCR and luciferase reporter assays were performed to determine the potential mechanism of ZNF655 regulating Aurora kinase A (AURKA). RESULTS ZNF655 was abundantly expressed in glioma tissue and cell lines SHG-44 and U251. Knockdown of suppressed the progression of glioma cells, which was characterized by reduced proliferation, enhanced apoptosis, cycle repression in G2, inhibition of migration, and weakened tumorigenesis. Mechanistically, transcription factor ZNF655 activated the expression of AURKA by directly binding to the promoter of AURKA. In addition, downregulation of AURKA partially reversed the promoting effects of overexpression of ZNF655 on glioma cells. CONCLUSIONS ZNF655 promoted the progression of glioma by binding to the promoter of AURKA, which may be a promising target for molecular therapy.
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Affiliation(s)
- Xu Chen
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, China
| | - Chao Liu
- Department of Neurosurgery of the First Affiliated Hospital of Zhengzhou University, Zhengzhou City, China
| | - Zhenyu Zhang
- Department of Neurosurgery of the First Affiliated Hospital of Zhengzhou University, Zhengzhou City, China
| | - Meng Wang
- Department of Neurosurgery of the First Affiliated Hospital of Zhengzhou University, Zhengzhou City, China
| | - Shewei Guo
- Department of Neurosurgery of the First Affiliated Hospital of Zhengzhou University, Zhengzhou City, China
| | - Tianhao Li
- Department of Neurosurgery of the First Affiliated Hospital of Zhengzhou University, Zhengzhou City, China
| | - Hongwei Sun
- Department of Neurosurgery of the First Affiliated Hospital of Zhengzhou University, Zhengzhou City, China
| | - Peng Zhang
- Department of Neurosurgery of the First Affiliated Hospital of Zhengzhou University, Zhengzhou City, China
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20
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Zhong Y, Zhuang Z, Mo P, Lin M, Gong J, Huang J, Mo H, Lu Y, Huang M. Overexpression of SKA3 correlates with poor prognosis in female early breast cancer. PeerJ 2022; 9:e12506. [PMID: 34993016 PMCID: PMC8675262 DOI: 10.7717/peerj.12506] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 10/26/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Spindle and kinetochore associated complex subunit 3 (SKA3) plays an important role in tumorigenesis and the progression of various tumors. But the relationship between SKA3 and early breast cancer remains unclear. The study aimed to explore the prognostic significance of SKA3 in breast cancer. METHODS In the study, SKA3 expression was initially assessed using the Oncomine database and The Cancer Genome Atlas database (TCGA). Then, we presented validation results for RT-qPCR (quantitative reverse transcription PCR) and ELISA (enzyme-linked immunosorbent assay). The relationship between clinical characteristics and SKA3 expression was assessed by Chi-square test and Fisher's exact test. Kaplan-Meier method and Cox regression analysis were conducted to evaluate the prognostic value of SKA3. Gene set enrichment analysis (GSEA) was performed to screen biological pathways using the TCGA dataset. Besides, single sample gene set enrichment analysis (ssGSEA) was utilized to identify immune infiltration cells about SKA3. RESULTS SKA3 mRNA was expressed at high levels in breast cancer tissues compared with normal tissues. Chi-square test and Fisher's exact test showed SKA3 expression was related to age, tumor (T) classification, node (N) classification, tumor-node-metastasis (TNM) stage, estrogen receptor (ER), progesterone receptor (PR), molecular subtype, and race. RT-qPCR results showed that SKA3 expression was overexpressed in ER, PR status, and molecular subtype in Chinese people. Kaplan-Meier curves implicated that high SKA3 expression was related to a poor prognosis in female early breast cancer patients. Cox regression models showed that high SKA3 expression could be used as an independent risk factor for female early breast cancer. Four signaling pathways were enriched in the high SKA3 expression group, including mTORC1 signaling pathway, MYC targets v1, mitotic spindle, estrogen response early. Besides, the SKA3 expression level was associate with infiltrating levels of activated CD4 T cells and eosinophils in breast cancer. CONCLUSION High SKA3 expression correlates with poor prognosis and immune infiltrates in breast cancer. SKA3 may become a biomarker for the prognosis of breast cancer.
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Affiliation(s)
- Yue Zhong
- Guangzhou University of Chinese Medicine, Guangzhou, China.,College of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhenjie Zhuang
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Peiju Mo
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Mandi Lin
- Galactophore Department, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiaqian Gong
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiarong Huang
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Haiyan Mo
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuyun Lu
- Galactophore Department, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Mei Huang
- Galactophore Department, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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21
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Deng Z, Huang K, Liu D, Luo N, Liu T, Han L, Du D, Lian D, Zhong Z, Peng J. Key Candidate Prognostic Biomarkers Correlated with Immune Infiltration in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2021; 8:1607-1622. [PMID: 34956967 PMCID: PMC8694277 DOI: 10.2147/jhc.s337067] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 11/18/2021] [Indexed: 12/29/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the most common subtype of primary liver cancer, which causes ~800,000 deaths annually world-wide. Immune checkpoint inhibitor (ICI) has reformed cancer therapy and achieved unprecedented results in various malignancies, including HCC. However, the response rate of immunotherapy is very low in HCC. Considereing the complicated and unique immune status in liver, we hypothesize that critical molecules will affect prognosis and correlate with immune context in the tumor microenvironment of HCC. Methods Using Kaplan–Meier plotter, GEPIA2 and Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB), survival genes and their prognostic value were estimated in HCC. Based on Tumor Immune Estimation Resource (TIMER), association between survival genes and immune infiltration was examined in HCC. FunRich and STRING were used to analyze gene ontology and protein–protein interaction (PPI) Network, qRT-PCR was used to measure mRNA level of candidates; and a Cell Counting Kit-8 was used to measure proliferation of HCC cell line. Results Using multiple databases, we identified 36 key prognostic genes highly expressed in HCC and associated with poor survival of patients. Meanwhile, the 36 gene signatures correlated with immune infiltration in HCC. Moreover, these genes were significantly associated with exhausted T cells and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in HCC. Among the 36 key genes, SKA3, SGOL2, SPINDOC, TEDC2, TMCO3 and NUP205 were highly expressed in tumor samples compared with adjacent normal tissues in our HCC cohort (n=22). Additionally, proliferation of SMMC7721 cell line was inhibited when it interfered with SiRNA of each gene. Conclusion The 36 genes may serve as potential prognostic biomarkers and molecular targets to ameliorate tumor immune microenvironment (TIME) in HCC and therefore represent a novel avenue for individualized immunotherapy in HCC.
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Affiliation(s)
- Zenghua Deng
- Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People's Republic of China.,Ninth School of Clinical Medicine, Peking University, Beijing, 100038, People's Republic of China
| | - Kanghua Huang
- Department of Radiation Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, People's Republic of China
| | - Dongfang Liu
- Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People's Republic of China
| | - Nan Luo
- Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People's Republic of China.,Ninth School of Clinical Medicine, Peking University, Beijing, 100038, People's Republic of China
| | - Tingting Liu
- Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People's Republic of China
| | - Long Han
- Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People's Republic of China
| | - Dexiao Du
- Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People's Republic of China
| | - Dongbo Lian
- Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People's Republic of China.,Ninth School of Clinical Medicine, Peking University, Beijing, 100038, People's Republic of China
| | - Zhaohui Zhong
- Department of General Surgery, Peking University People's Hospital, Beijing, 100044, People's Republic of China
| | - Jirun Peng
- Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People's Republic of China.,Ninth School of Clinical Medicine, Peking University, Beijing, 100038, People's Republic of China
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22
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Bozic D, Baralić K, Živančević K, Miljaković EA, Ćurčić M, Antonijević B, Djordjević AB, Bulat Z, Zhang Y, Yang L, Đukić-Ćosić D. Predicting sulforaphane-induced adverse effects in colon cancer patients via in silico investigation. Biomed Pharmacother 2021; 146:112598. [PMID: 34959120 DOI: 10.1016/j.biopha.2021.112598] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 12/17/2021] [Accepted: 12/23/2021] [Indexed: 01/14/2023] Open
Abstract
Colorectal cancer (CRC) is a significant global health burden that ranks as the third most diagnosed and second most common cause of cancer related deaths worldwide. New therapeutic strategies include chemoprevention and use of molecules which could prevent, suppress or reverse CRC progression such as sulforaphane (SFN). However, evidences about its safety in CRC patients are still lacking. The aim of this in silico investigation was to predict SFN-induced adverse effects in CRC patients by computational analysis. The study showed that 334 genes were consistently dysregulated in CRC (223 downregulated and 111 upregulated), while 38 were recognized as significant and might be used as predictive biomarkers for overall survival and metastasis (TCGA, GEO, R studio). Among them, SFN interacted with 86 genes, out of which 11 were marked as significant (correlate with overall prognosis and metastasis). Sulforaphane potentiates the overexpression of TIMP1, AURKA, and CEP55, and promotes inhibition of CRYAB, PLCE1, and MMP28, that might lead to the progression of CRC (CTD). Pathway enrichment analysis revealed that SFN stimulated Transcriptional activation of RUNX2, AURKA activation by TPX2, IL-10 signaling, while inhibited Differentiation of White and Brown Adipocyte process, an underlying pathway which inactivation led to obesity (Cytoscape ClueGo + CluePedia, DAVID). Thus, genome signature of CRC patients could serve as important factor when addressing the risk-to-benefit profile of SFN. Patients with colon cancer and increased expression of TIMP1, CCL20, SPP1, AURKA, CEP55, NEK2, SOX9 and CDK1, or downregulation of CRYAB, PLCE1, MMP28, BMP2 and PLAC8 may not be ideal candidates for SFN chemoprevention.
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Affiliation(s)
- Dragica Bozic
- Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia; Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe Road, Zhengzhou 450052, Henan, China.
| | - Katarina Baralić
- Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
| | - Katarina Živančević
- Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
| | - Evica Antonijević Miljaković
- Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia; Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
| | - Marijana Ćurčić
- Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia; Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
| | - Biljana Antonijević
- Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia; Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
| | - Aleksandra Buha Djordjević
- Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia; Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
| | - Zorica Bulat
- Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia; Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
| | - Yi Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe Road, Zhengzhou 450052, Henan, China
| | - Li Yang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe Road, Zhengzhou 450052, Henan, China
| | - Danijela Đukić-Ćosić
- Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia; Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
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23
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Xiao J, Zhang Y. AURKB as a Promising Prognostic Biomarker in Hepatocellular Carcinoma. Evol Bioinform Online 2021; 17:11769343211057589. [PMID: 34866894 PMCID: PMC8637395 DOI: 10.1177/11769343211057589] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 10/18/2021] [Indexed: 12/24/2022] Open
Abstract
The Aurora kinases form a family of 3 genes encoding serine/threonine kinases and are involved in the regulation of cell division during the mitosis. This study was designed to investigate the prognostic role of Aurora kinases in hepatocellular carcinoma (HCC). In this study, we analyzed the expression, overall survival (OS) data, promoter methylation level, and relationship with immunoinhibitors of Aurora kinases in patients with HCC from GEPIA2, UALCAN, OncoLnc, and TISIDB databases. Protein-protein interaction (PPI) network, gene ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway analysis were performed using the STRING database and Cytoscape software. We found that the mRNA expression, stages of HCC, and OS of AURKA and AURKB in HCC tissues were significantly different from control tissues, but there were significant inconsistencies in promoter methylation level and relationship with immunoinhibitors for AURKA and AURKB. None of the above items were significantly different for AURKC. Furthermore, a hub module including AURKA, AURKB, and AURKC was identified within the PPI network constructed with the Molecular Complex Detection (MCODE) plug-in in Cytoscape software. Our results show that AURKB could be a potential biomarker for HCC prognosis.
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Affiliation(s)
- Jingchuan Xiao
- Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, Hainan, China
| | - Yingai Zhang
- Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, Hainan, China.,School of Life Sciences, Hainan University, Haikou, Hainan, China
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24
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Ding J, He X, Wang J, Cao G, Chen S, Yuan L, Chen B, Xiong M. Integrative analysis of prognostic value and immune infiltration of spindle and kinetochore-associated family members in breast cancer. Bioengineered 2021; 12:10905-10923. [PMID: 34845974 PMCID: PMC8809973 DOI: 10.1080/21655979.2021.1995576] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
Spindle and kinetochore associated (SKA) complex subunit, which maintains the stability of mitotic metaphase, with emerging research implying its effect as a carcinogenic regulator in cancer. However, its potential role in BC has not been fully elucidated. ONCOMINE, UALCAN, GEPIA, Kaplan-Meier Plotter, cBioPortal and TIMER databases were performed to analyze the expression, prognosis, mutation, immune infiltration and potential biological mechanisms of SKA1/2/3 in BC. Our results showed that SKA1/2/3 expression was upregulated in BC. Survival analysis reveals that SKA3 overexpression was associated with poor overall survival (OS), relapse-free survival (RFS), post-progression survival (PPS) and distant metastasis-free survival (DMFS). SKA1 overexpression was associated with poor OS, RFS and DMFS while SKA2 overexpression was only associated with RFS and DMFS. Notably, the results implied that SKA1 has a good prognostic value in HER2-positive BC. Besides, the genetic alterations of SKA were investigated and the altered group correlated with shorter progress-free survival (PFS) and disease-specific survival (DSS). GO and KEGG analysis showed that SKA1/2/3 were implicated in regulating cell cycle, p53 signaling pathway and DNA replication. The 10 Hub genes in the protein network were upregulated in BC and related to poorer prognosis. Additionally, SKA1/2/3 expression was negatively correlated with infiltration of various immune cells with antitumor effects, whereas positively correlated with the expression of immune checkpoints molecules. Further experiments revealed that SKA1/2/3 silencing markedly impeded the proliferation and migration of BC cells. Herein, our study firmly shows that SKA genes may serve as a promising therapeutic target for patients with BC.
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Affiliation(s)
- Jianfeng Ding
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.,Department of General Surgery, Chaohu Hospital of Anhui Medical University, Chaohu, Anhui, China
| | - Xiaobo He
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Jinkun Wang
- Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Guodong Cao
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Sihan Chen
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Liping Yuan
- Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Bo Chen
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Maoming Xiong
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.,Department of General Surgery, Chaohu Hospital of Anhui Medical University, Chaohu, Anhui, China
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25
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Liang Y, Zheng Y, Mou K, Han D, Wang L, Ge R, Meng A. Inhibition of spindle and kinetochore associated complex subunit 3 suppresses the proliferation and invasion and induced the apoptosis of cutaneous melanoma by affecting the PI3K/Akt pathway. J Biochem Mol Toxicol 2021; 35:e22895. [PMID: 34423490 DOI: 10.1002/jbt.22895] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 05/28/2021] [Accepted: 08/13/2021] [Indexed: 11/11/2022]
Abstract
Spindle and kinetochore-associated complex subunit 3 (SKA3) is reportedly a key contributor to the progression of various cancers. The present work aimed to evaluate the possible role of SKA3 in cutaneous melanoma (CM). A high SKA3 level was found in CM tissues and predicted a poor prognosis. SKA3 silencing markedly repressed the proliferation, invasion, and epithelial-mesenchymal transition and induced the apoptosis of CM cells. SKA3 silencing decreased the phosphorylation of PI3K and Akt. Akt inhibition markedly reversed SKA3 overexpression-induced oncogenic effects on CM cells. SKA3 silencing significantly prohibited the formation and growth of CM-derived xenograft tumors in nude mice in vivo. Our findings demonstrated SKA3 inhibition repressed the progression of CM by downregulating the PI3K/Akt pathway. This study indicates that SKA3 has potential as an anticancer candidate for CM.
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Affiliation(s)
- Yan Liang
- Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yan Zheng
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Kuanhou Mou
- Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Dan Han
- Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Lijuan Wang
- Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Rui Ge
- Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Anfeng Meng
- Department of Plastic Surgery, The Municipal People's Hospital of Baoji, Baoji, China
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26
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Zhang M, Lan X, Chen Y. MiR-133b suppresses the proliferation, migration and invasion of lung adenocarcinoma cells by targeting SKA3. Cancer Biol Ther 2021; 22:571-578. [PMID: 34711122 DOI: 10.1080/15384047.2021.1973819] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Spindle and Kinetochore Associated Complex Subunit 3 (SKA3) is crucial for anaphase mitosis. However, the relationship between SKA3 and lung adenocarcinoma (LUAD) has not been fully clarified. Differentially expressed genes were first identified by analyzing data from TCGA. It was found that miR-133b was significantly lowly expressed in LUAD, while SKA3 was remarkably highly expressed. Cell Counting Kit-8 (CCK8), wound healing assay and Transwell assay uncovered that overexpressing miR-133b could inhibit the proliferation, invasion and migration of LUAD cells. In addition, the targeting relationship between miR-133b and SKA3 was also verified by dual-luciferase analysis. Moreover, it was proved by the rescue assay that the overexpression of miR-133b significantly downregulated SKA3 in LUAD cells. All in all, these findings revealed the role of miR-133b and SKA3 in regulating the proliferation, migration, and invasion of LUAD cells. This study could yield new information about the mechanisms of LUAD.
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Affiliation(s)
- Ming Zhang
- Department of Respiratory, The First Hospital of Jiaxing (The Affiliated Hospital of Jiaxing University), Jiaxing, Zhejiang PR China
| | - Xiang Lan
- Department of Radiation Oncology, Lishui City People's Hospital, Lishui, Zhejiang PR China
| | - Yong Chen
- Department of Radiation Oncology, Lishui City People's Hospital, Lishui, Zhejiang PR China
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27
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Hub Genes and Key Pathways of Intervertebral Disc Degeneration: Bioinformatics Analysis and Validation. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5340449. [PMID: 34545328 PMCID: PMC8449732 DOI: 10.1155/2021/5340449] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 08/25/2021] [Indexed: 01/04/2023]
Abstract
Objective To identify significant pathways and genes in intervertebral disc degeneration (IDD) based on bioinformatics analysis. Design The GEO database was used to download the GSE124272 dataset. Differentially expressed genes (DEGs) were analyzed using Limma package in R language. Then, gene ontologies (GO), Kyoto encyclopedia of genes and genomes (KEGG), and protein-protein interaction (PPI) networks were used to further identify hub genes. The mRNA expression levels of top six hub genes were verified. Results We found 563 DEGs, of which 214 were upregulated and 349 were downregulated. The top 5 GO terms and pathways were shown including immune response, cell cycle, and p53 pathway. Based on the PPI analysis, we verified the mRNA expression levels of 6 hub genes. The mRNA levels of CHEK1, CDCA2, SKA3, and KIF20A were upregulated in degenerative NP tissue than in healthy NP tissue. However, the mRNA level of BUB1 and SPC25 was downregulated. Conclusions This study may provide new biomarkers for the IDD and treatments to repair IDD related to CHEK1, CDCA2, SKA3, BUB1, KIF20A, and SPC25.
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Integrative Transcriptome Profiling Reveals SKA3 as a Novel Prognostic Marker in Non-Muscle Invasive Bladder Cancer. Cancers (Basel) 2021; 13:cancers13184673. [PMID: 34572901 PMCID: PMC8470398 DOI: 10.3390/cancers13184673] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/03/2021] [Accepted: 09/14/2021] [Indexed: 01/03/2023] Open
Abstract
Approximately 80% of all new bladder cancer patients are diagnosed with non-muscle invasive bladder cancer (NMIBC). However, approximately 15% of them progress to muscle-invasive bladder cancer (MIBC), for which prognosis is poor. The current study aimed to improve diagnostic accuracy associated with clinical outcomes in NMIBC patients. Nevertheless, it has been challenging to identify molecular biomarkers that accurately predict MIBC progression because this disease is complex and heterogeneous. Through integrative transcriptome profiling, we showed that high SKA3 expression is associated with poor clinical outcomes and MIBC progression. We performed RNA sequencing on human tumor tissues to identify candidate biomarkers in NMIBC. We then selected genes with prognostic significance by analyzing public datasets from multiple cohorts of bladder cancer patients. We found that SKA3 was associated with NMIBC pathophysiology and poor survival. We analyzed public single-cell RNA-sequencing (scRNA-seq) data for bladder cancer to dissect transcriptional tumor heterogeneity. SKA3 was expressed in an epithelial cell subpopulation expressing genes regulating the cell cycle. Knockdown experiments confirmed that SKA3 promotes bladder cancer cell proliferation by accelerating G2/M transition. Hence, SKA3 is a new prognostic marker for predicting NMIBC progression. Its inhibition could form part of a novel treatment lowering the probability of bladder cancer progression.
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Xie L, Cheng S, Fan Z, Sang H, Li Q, Wu S. SKA3, negatively regulated by miR-128-3p, promotes the progression of non-small-cell lung cancer. Per Med 2021; 19:193-205. [PMID: 34533066 DOI: 10.2217/pme-2020-0095] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Aim: To investigate the effects of SKA3 on cell proliferation and metastasis in non-small-cell lung cancer (NSCLC) and its underlying mechanism. Methods: Immunohistochemistry was employed to analyze the expression of SKA3 in NSCLC. CCK-8 assay, EdU assay, Transwell assay and flow cytometry analysis were employed to assess cell proliferation, metastatic potential and apoptosis in vitro, respectively. A lung metastasis model was used to evaluate metastasis of NSCLC cells in vivo. A luciferase reporter gene assay was conducted to verify the targeting relationship. Results: SKA3 exhibited high expression in NSCLC tissues and cells. Overexpression of SKA3 remarkably accelerated cell proliferation and metastasis and suppressed apoptosis of NSCLC cells and promoted lung metastasis in a mouse model. miR-128-3p repressed SKA3 expression by targeting it. Conclusion: miR-128-3p inhibited the progression of NSCLC through targeting SKA3.
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Affiliation(s)
- Linlin Xie
- Department of Foundation Courses, Anhui Medical College, Hefei, 230601, China
| | - Shaofei Cheng
- Department of Thoracic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 201308, China
| | - Zhengyang Fan
- Department of Thoracic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 201308, China
| | - Hongyang Sang
- Department of Thoracic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 201308, China
| | - Qianping Li
- Department of Thoracic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 201308, China
| | - Song Wu
- Department of Thoracic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 201308, China
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Miralaei N, Majd A, Ghaedi K, Peymani M, Safaei M. Integrated pan-cancer of AURKA expression and drug sensitivity analysis reveals increased expression of AURKA is responsible for drug resistance. Cancer Med 2021; 10:6428-6441. [PMID: 34337875 PMCID: PMC8446408 DOI: 10.1002/cam4.4161] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 07/11/2021] [Accepted: 07/12/2021] [Indexed: 12/11/2022] Open
Abstract
Introduction The AURKA gene encodes a protein kinase involved in cell cycle regulation and plays an oncogenic role in many cancers. The main objective of this study is to analyze AURKA expression in 13 common cancers and its role in prognostic and drug resistance. Method Using the cancer genome atlas (TCGA) as well as CCLE and GDSC data, the level of AURKA gene expression and its role in prognosis and its association with drug resistance were evaluated, respectively. In addition, the expression level of AURKA was assessed in colorectal cancer (CRC) and gastric cancer (GC) samples. Besides, using Gene Expression Omnibus (GEO) data, drugs that could affect the expression level of this gene were also identified. Results The results indicated that the expression level of AURKA gene in 13 common cancers increased significantly compared to normal samples or it survived poorly (HR >1, p < 0.01) in lung, prostate, kidney, bladder, and uterine cancers. Also, the gene expression data showed increased expression in CRC and GC samples compared to normal ones. The level of AURKA was significantly associated with the resistance to SB 505124, NU‐7441, and irinotecan drugs (p < 0.01). Eventually, GEO data showed that JQ1, actinomycin D1, and camptothecin could reduce the expression of AURKA gene in different cancer cell lines (logFC < 1, p < 0.01). Conclusion Increased expression of AURKA is observed in prevalent cancers and associated with poor prognostic and the development of drug resistance. In addition, some chemotherapy drugs can reduce the expression of this gene.
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Affiliation(s)
- Noushin Miralaei
- Department of Biology, Tehran North Branch, Islamic Azad University, Tehran, Iran
| | - Ahmad Majd
- Department of Biology, Tehran North Branch, Islamic Azad University, Tehran, Iran
| | - Kamran Ghaedi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Maryam Peymani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Masoomeh Safaei
- Department of Pathology, Cancer Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
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Das BK, Kannan A, Nguyen Q, Gogoi J, Zhao H, Gao L. Selective Inhibition of Aurora Kinase A by AK-01/LY3295668 Attenuates MCC Tumor Growth by Inducing MCC Cell Cycle Arrest and Apoptosis. Cancers (Basel) 2021; 13:3708. [PMID: 34359608 PMCID: PMC8345130 DOI: 10.3390/cancers13153708] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/17/2021] [Accepted: 07/20/2021] [Indexed: 12/31/2022] Open
Abstract
Merkel cell carcinoma (MCC) is an often-lethal skin cancer with increasing incidence and limited treatment options. Although immune checkpoint inhibitors (ICI) have become the standard of care in advanced MCC, 50% of all MCC patients are ineligible for ICIs, and amongst those treated, many patients develop resistance. There is no therapeutic alternative for these patients, highlighting the urgent clinical need for alternative therapeutic strategies. Using patient-derived genetic insights and data generated in our lab, we identified aurora kinase as a promising therapeutic target for MCC. In this study, we examined the efficacy of the recently developed and highly selective AURKA inhibitor, AK-01 (LY3295668), in six patient-derived MCC cell lines and two MCC cell-line-derived xenograft mouse models. We found that AK-01 potently suppresses MCC survival through apoptosis and cell cycle arrest, particularly in MCPyV-negative MCC cells without RB expression. Despite the challenge posed by its short in vivo durability upon discontinuation, the swift and substantial tumor suppression with low toxicity makes AK-01 a strong potential candidate for MCC management, particularly in combination with existing regimens.
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Affiliation(s)
- Bhaba K. Das
- Southern California Institute for Research and Education, Long Beach, CA 90822, USA; (B.K.D.); (J.G.); (H.Z.)
- Veterans Affairs Long Beach Healthcare System, Long Beach, CA 90822, USA;
| | - Aarthi Kannan
- Veterans Affairs Long Beach Healthcare System, Long Beach, CA 90822, USA;
- Department of Dermatology, University of California, Irvine, CA 92697, USA
| | - Quy Nguyen
- Genomics High Throughput Sequencing Facility, Department of Biological Chemistry, University of California, Irvine, CA 92697, USA;
| | - Jyoti Gogoi
- Southern California Institute for Research and Education, Long Beach, CA 90822, USA; (B.K.D.); (J.G.); (H.Z.)
| | - Haibo Zhao
- Southern California Institute for Research and Education, Long Beach, CA 90822, USA; (B.K.D.); (J.G.); (H.Z.)
- Veterans Affairs Long Beach Healthcare System, Long Beach, CA 90822, USA;
| | - Ling Gao
- Southern California Institute for Research and Education, Long Beach, CA 90822, USA; (B.K.D.); (J.G.); (H.Z.)
- Veterans Affairs Long Beach Healthcare System, Long Beach, CA 90822, USA;
- Department of Dermatology, University of California, Irvine, CA 92697, USA
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Peng Q, Wen T, Liu D, Wang S, Jiang X, Zhao S, Huang G. DSN1 is a prognostic biomarker and correlated with clinical characterize in breast cancer. Int Immunopharmacol 2021; 101:107605. [PMID: 34238686 DOI: 10.1016/j.intimp.2021.107605] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 03/02/2021] [Accepted: 03/05/2021] [Indexed: 11/20/2022]
Abstract
DSN1 affects cell cycle progression and is associated with clinical-pathological features in colorectal and hepatocellular carcinomas. However, the biological function of DSN1 in breast cancer is still indistinct. In this study, we comprehensively analyzed the correlation between DSN1 expression in different molecular subtypes or stages of breast cancer and investigated the prognostic value of DSN1 in databases such as Oncomine, Cancer Cell Line Encyclopedia, UALCAN, Human Protein Atlas, Kaplan-Meier Plotter, OncoLnc, GEPIA. Moreover, we investigated the correlation of DSN1 with tumor-infiltrating immune cells in the different tumor microenvironments via Tumor Immune Estimation Resource database and explore DSN1 co-expression networks in breast cancer via LinkedOmics analysis, NetworkAnalyst database analysis. Finally, we also performed our immunohistochemical experiments to explore the expression of DSN1 in different stages or subtypes of breast cancer. The findings in this article shed light on the essential role of DSN1 in breast cancers as well as suggested that the upregulation of DSN1 expression was strongly associated with poor prognosis and decreased survival in breast cancer, and there were significant differences in its expression in different pathological subtypes and stages of breast cancer.
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Affiliation(s)
- Qing Peng
- Department of VIP clinic, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, PR China.
| | - Tingyu Wen
- Department of Medical Oncology, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
| | - Dongyang Liu
- Division of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, PR China.
| | - Suguo Wang
- Department of VIP clinic, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, PR China
| | - Xinting Jiang
- Department of VIP clinic, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, PR China
| | - Shiju Zhao
- Department of VIP clinic, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, PR China.
| | - Gaozhong Huang
- Department of VIP clinic, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, PR China.
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Li FN, Zhang QY, Li O, Liu SL, Yang ZY, Pan LJ, Zhao C, Gong W, Shu YJ, Dong P. ESRRA promotes gastric cancer development by regulating the CDC25C/CDK1/CyclinB1 pathway via DSN1. Int J Biol Sci 2021; 17:1909-1924. [PMID: 34131395 PMCID: PMC8193261 DOI: 10.7150/ijbs.57623] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 04/29/2021] [Indexed: 02/05/2023] Open
Abstract
Background: Estrogen-related receptor-α (ESRRA) is an orphan nuclear receptor, expressing at high level in exuberant metabolism organs and acting as transcription factor. High expression was found in many malignances but no research was done in gastric cancer (GC), where lipid metabolism disorder is common. Methods: Kaplan-Meier plot was utilized to find the relationship between ESRRA expression and patients' prognoses. The expression level of ESRRA was measured by real-time PCR. The protein expression levels were tested with western-blot and immunohistochemistry. Cell cycle and apoptosis was identified with flow cytometry. RNA-seq, bioinformatics analysis, dual-luciferase assay and ChIP assay were used to predict and validate ESRRA's target gene and binding motif. Animal models were also introduced in our study. Results: ESRRA expression is notably higher in GC cell lines and high ESRRA levels are correlated to poor prognoses. ESRRA silencing decreased GC cell viability, migration, and invasion capacities. Its downstream gene DSN1 was spotted by RNA-seq and confirmed by later bioinformatics analyses, dual-luciferase, and ChIP assays. Western-blot showed G2M arrest caused by ESRRA silencing was via CDC25C-CDK1-Cyclin B1 pathway. Conclusion: ESRRA/DSN1/CDC25C-CDK1-Cyclin B1 is of great importance in GC development. ESRRA could be a potential target as well as prognostic marker in GC.
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Affiliation(s)
- Feng-Nan Li
- Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Qin-Yi Zhang
- Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Ou Li
- Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Shi-Lei Liu
- Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Zi-Yi Yang
- Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Li-Jia Pan
- Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Cheng Zhao
- Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Wei Gong
- Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Yi-Jun Shu
- Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Ping Dong
- Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China, No. 1665 Kongjiang Road, Shanghai 200092, China
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Li C, Yang J, Lei S, Wang W. SKA3 promotes glioblastoma proliferation and invasion by enhancing the activation of Wnt/β-catenin signaling via modulation of the Akt/GSK-3β axis. Brain Res 2021; 1765:147500. [PMID: 33895155 DOI: 10.1016/j.brainres.2021.147500] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 03/22/2021] [Accepted: 04/18/2021] [Indexed: 12/31/2022]
Abstract
Spindle and kinetochore-related complex subunit 3 (SKA3) is a key modulator of the progression of multiple tumor types. However, the involvement of SKA3 in glioblastoma (GBM) has not been well studied. The current study aimed to explore the role of SKA3 expression and the potential function of the protein in GBM. Our data showed that SKA3 expression was significantly up-regulated in GBM. Functional assays demonstrated that the knockdown of SKA3 impeded the proliferation, colony formation and invasion of GBM cells, while SKA3 overexpression produced the opposite effects. Further investigation revealed that SKA3 overexpression enhanced the activation of Wnt/β-catenin signaling, which was associated with the enhanced phosphorylation of Akt and glycogen synthase kinase-3β (GSK-3β). Notably, the inhibition of Akt markedly abrogated the SKA3 overexpression-induced promotion of Wnt/β-catenin signaling in GBM cells. Further, the inhibition of Wnt/β-catenin signaling markedly abrogated the SKA3 overexpression-induced promotion of tumor growth. In addition, the knockdown of SKA3 significantly retarded tumor formation and GBM progression in vivo. In summary, these data demonstrate that SKA3 exerts promotes tumor growth in GBM by enhancing the activation of Wnt/β-catenin signaling via modulation of the Akt/GSK-3β axis. This work highlights the pivotal role of SKA3/Akt/GSK-3β/Wnt/β-catenin signaling in the progression of GBM and suggests that SKA3 is an attractive therapeutic target with potential to be used to treat GBM.
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Affiliation(s)
- Chuankun Li
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
| | - Jingya Yang
- Department of Operation, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Sen Lei
- Department of Anus and Intestine Surgery, ZiBo Central Hospital, Zibo 255036, China
| | - Wei Wang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
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Liu F, Zhang Y, Dong Y, Ning P, Zhang Y, Sun H, Li G. Knockdown of AURKA sensitizes the efficacy of radiation in human colorectal cancer. Life Sci 2021; 271:119148. [PMID: 33545203 DOI: 10.1016/j.lfs.2021.119148] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 01/18/2021] [Accepted: 01/22/2021] [Indexed: 01/06/2023]
Abstract
AIMS Abnormally amplified expression of AURKA (aurora kinase A) is closely related to chemo-resistance in human colorectal cancer, lung cancer and leukemia. However, the biological role of AURKA in response to radio-sensitivity in human colorectal cancer is still unknown. Therefore, we evaluated the radio-sensitize ability of perturbation AURKA in human colorectal cancer. MAIN METHODS The knockdown effect of shAURKA was determined by western blot and qRT-PCR, respectively. Cell growth was determined by CCK-8 and clonogenic assay. Cell migration and metastasis was measured by wound healing assay and transwell invasive assay, respectively. Cell cycle and apoptosis was analyzed by flow cytometry. The alteration of down-stream targets was determined by western blot analysis. KEY FINDINGS We observed that high-level of AURKA expression is associated with poor prognosis in CRC patients receiving radiotherapy. Knockdown of AURKA significantly sensitizes the efficacy of radiation on the proliferation of HCT116 and HT-29 cells. The combination of AURKA inhibition and radiation could effectively suppress the ability of cell migration and metastasis, but also synergistically induce cellular apoptosis and arrest cell cycle at G2/M phase. Further studies demonstrated that knockdown AURKA markedly enhanced the efficacy of radiation through elevated PARP cleavage and induced AURKA-mediated pro-apoptosis factor BIM. Meanwhile, knockdown of AURKA in combination with radiation synergistically suppressed the regulator in blockage of G2/M phase, CDK2. SIGNIFICANCE Taken together, our results provide the evidence that targeted inhibition of AURKA could be a promising strategy for enhancing the efficacy of radiation for the treatment of human colorectal cancer.
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Affiliation(s)
- Fei Liu
- Department of Radiation Oncology, The First Affiliated Hospital of China Medical University, China
| | - Yong Zhang
- Department of Pathology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, China
| | - Yue Dong
- Department of Radiology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, China
| | - Peifang Ning
- Department of Pathology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, China
| | - Yanni Zhang
- Department of Radiation Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, China
| | - Han Sun
- Department of Radiation Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, China
| | - Guang Li
- Department of Radiation Oncology, The First Affiliated Hospital of China Medical University, China.
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Wang Z, Guo M, Ai X, Cheng J, Huang Z, Li X, Chen Y. Identification of Potential Diagnostic and Prognostic Biomarkers for Colorectal Cancer Based on GEO and TCGA Databases. Front Genet 2021; 11:602922. [PMID: 33519906 PMCID: PMC7841465 DOI: 10.3389/fgene.2020.602922] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 11/30/2020] [Indexed: 01/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common neoplastic diseases worldwide. With a high recurrence rate among all cancers, treatment of CRC only improved a little over the last two decades. The mortality and morbidity rates can be significantly lessened by earlier diagnosis and prompt treatment. Available biomarkers are not sensitive enough for the diagnosis of CRC, whereas the standard diagnostic method, endoscopy, is an invasive test and expensive. Hence, seeking the diagnostic and prognostic biomarkers of CRC is urgent and challenging. With that order, we screened the overlapped differentially expressed genes (DEGs) of GEO (GSE110223, GSE110224, GSE113513) and TCGA datasets. Subsequent protein-protein interaction network analysis recognized the hub genes among these DEGs. Further functional analyses including Gene Ontology and KEGG pathway analysis and gene set enrichment analysis were processed to investigate the role of these genes and potential underlying mechanisms in CRC. Kaplan-Meier analysis and Cox hazard ratio analysis were carried out to clarify the diagnostic and prognostic role of these genes. In conclusion, our present study demonstrated that CCNA2, MAD2L1, DLGAP5, AURKA, and RRM2 are all potential diagnostic biomarkers for CRC and may also be potential treatment targets for clinical implication in the future.
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Affiliation(s)
- Zhenjiang Wang
- Department of Gastroenterology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated With Jinan University), Zhuhai, China
| | - Mingyi Guo
- Department of Gastroenterology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated With Jinan University), Zhuhai, China
| | - Xinbo Ai
- Department of Gastroenterology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated With Jinan University), Zhuhai, China
| | - Jianbin Cheng
- Department of Gastroenterology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated With Jinan University), Zhuhai, China
| | - Zaiwei Huang
- Department of Gastroenterology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated With Jinan University), Zhuhai, China
| | - Xiaobin Li
- Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai Hospital Affiliated With Jinan University), Zhuhai, China
| | - Yuping Chen
- Department of Gastroenterology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated With Jinan University), Zhuhai, China
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Spindle and kinetochore‑associated complex subunit 3 accelerates breast cancer cell proliferation and invasion through the regulation of Akt/Wnt/β-catenin signaling. Breast Cancer Res Treat 2021; 186:247-258. [PMID: 33423159 DOI: 10.1007/s10549-020-06078-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 12/23/2020] [Indexed: 12/24/2022]
Abstract
PURPOSE Spindle and kinetochore‑associated complex subunit 3 (SKA3) has recently been identified as a novel regulator of carcinogenesis in multiple types of cancers. However, the function and potential regulatory mechanisms of SKA3 in breast cancer remain poorly understood. The present study was designed to gain a detailed relevance of SKA3 in breast cancer. METHODS Expression of SKA3 in breast cancer was examined via real-time quantitative PCR, western blotting and immunohistochemistry analysis. Malignant behaviors of breast cancer cells were investigated via cell counting kit-8, cell apoptosis, and transwell invasion assays. The activity of Wnt/β-catenin signaling was monitored via luciferase reporter assay. The tumorigenicity of breast cancer cells in vivo was assessed via xenograft tumor assay. RESULTS SKA3 expression was elevated in breast cancer tissue and was correlated with shorter survival rates in breast cancer patients. Knockdown of SKA3 caused marked reductions in cellular proliferation and invasion in breast cancer cells, whereas SKA3 overexpression accelerated proliferation and invasion. Knockdown of SKA3 resulted in decreased Akt and glycogen synthase kinase-3β phosphorylation, and decreased expression of active β-catenin, which lead to the inactivation of Wnt/β-catenin signaling. Inhibition of Akt significantly reversed the SKA3 overexpression-induced activation of Wnt/β-catenin signaling. Inhibition of Wnt/β-catenin signaling markedly abrogated SKA3 overexpression-induced tumor-promotion effects, while re-activation of Wnt/β-catenin signaling significantly reversed SKA3 knockdown-mediated tumor-inhibition effects. Knockdown of SKA3 resulted in a significant decrease in breast cancer tumor formation in vivo. CONCLUSIONS SKA3 accelerates proliferation and invasion in breast cancer through the modulation of Akt/Wnt/β-catenin signaling.
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Tang J, Yang L, Li Y, Ning X, Chaulagain A, Wang T, Wang D. ARID3A promotes the development of colorectal cancer by upregulating AURKA. Carcinogenesis 2020; 42:578-586. [PMID: 33165575 DOI: 10.1093/carcin/bgaa118] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 10/27/2020] [Accepted: 10/31/2020] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumours, and its morbidity and mortality rates are relatively high. However, the aetiology and pathogenesis of CRC have not been clearly elucidated to date. AT-rich interaction domain 3A (ARID3A) is a member of the ARID3 family and a transcription factor that can bind to specific DNA sites to regulate gene expression. It was reported that ARID3A is involved in various biological processes and may be related to carcinogenesis. In this study, by assessing the mRNA level of ARID3A in TCGA database, we found that ARID3A expression increased in CRC tissues, and proposed that ARID3A could act as a tumour-promoting factor in the development of CRC. To verify this hypothesis, we used cell proliferation, migration and invasion assays to assess the effect of ARID3A on CRC cells. We revealed that ARID3A overexpression enhanced tumour cell proliferation, migration and invasion. ARID3A could target Aurora kinase A (AURKA) to facilitate the malignant phenotype of CRC cells, and patients with a higher ratio of AURKA and ARID3A had a better overall survival. Conclusively, this study showed that ARID3A targeted AURKA to facilitate the development of CRC. The ratio of ARID3A and AURKA could be used as a potential biomarker to predict prognosis, providing a new strategy for the diagnosis and prognosis of CRC.
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Affiliation(s)
- Jing Tang
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Pathology, Harbin Medical University, Harbin, China
| | - Lirui Yang
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Yafei Li
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Xuelian Ning
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Anita Chaulagain
- Department of Microbiology, Harbin Medical University, Harbin, China
| | - Tianzhen Wang
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Dong Wang
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Dermatology Hospital, Southern Medical University, Guangzhou, China.,Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, China
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Lyu J, Yang EJ, Zhang B, Wu C, Pardeshi L, Shi C, Mou PK, Liu Y, Tan K, Shim JS. Synthetic lethality of RB1 and aurora A is driven by stathmin-mediated disruption of microtubule dynamics. Nat Commun 2020; 11:5105. [PMID: 33037191 PMCID: PMC7547687 DOI: 10.1038/s41467-020-18872-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 09/16/2020] [Indexed: 11/13/2022] Open
Abstract
RB1 mutational inactivation is a cancer driver in various types of cancer including lung cancer, making it an important target for therapeutic exploitation. We performed chemical and genetic vulnerability screens in RB1-isogenic lung cancer pair and herein report that aurora kinase A (AURKA) inhibition is synthetic lethal in RB1-deficient lung cancer. Mechanistically, RB1-/- cells show unbalanced microtubule dynamics through E2F-mediated upregulation of the microtubule destabilizer stathmin and are hypersensitive to agents targeting microtubule stability. Inhibition of AURKA activity activates stathmin function via reduced phosphorylation and facilitates microtubule destabilization in RB1-/- cells, heavily impacting the bipolar spindle formation and inducing mitotic cell death selectively in RB1-/- cells. This study shows that stathmin-mediated disruption of microtubule dynamics is critical to induce synthetic lethality in RB1-deficient cancer and suggests that upstream factors regulating microtubule dynamics, such as AURKA, can be potential therapeutic targets in RB1-deficient cancer.
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Affiliation(s)
- Junfang Lyu
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China
| | - Eun Ju Yang
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China
| | - Baoyuan Zhang
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China
| | - Changjie Wu
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China
| | - Lakhansing Pardeshi
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China
| | - Changxiang Shi
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China
| | - Pui Kei Mou
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China
| | - Yifan Liu
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China
| | - Kaeling Tan
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China
| | - Joong Sup Shim
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China.
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Lu H, Zhu Q. Identification of Key Biological Processes, Pathways, Networks, and Genes with Potential Prognostic Values in Hepatocellular Carcinoma Using a Bioinformatics Approach. Cancer Biother Radiopharm 2020; 36:837-849. [PMID: 32598174 DOI: 10.1089/cbr.2019.3327] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Aim: Hepatocellular carcinoma (HCC), as one primary liver cancer type, accounts for 75%-85% of liver cancer cases. HCC is the second leading cause of cancer death in East Asia and sub-Saharan Africa and the sixth most common in western countries. Identification of key genes would facilitate the development of therapies and improve the prognosis outcomes of HCC patients. This study was to identify the key biological processes, pathways, and key genes in HCC. Methods: Data were downloaded from Broad GDAC. Differentially expressed genes (DEGs) and weighted gene coexpression network (WGCNA) were analyzed by DESeq2 and WGCNA, respectively. Gene ontology (GO) and KEGG enrichment analyses were performed on all DEGs and the coexpressed genes in two significant modules. Kaplan-Meier plotter online database was used to identify the potential prognostic genes in HCC. Finally, GEO database was used to validate the analysis of gene expression of Broad GDAC data. Results: The authors identified the dark gray and red modules as the significant modules in HCC based on WGCNA. GO and KEGG enrichment of the two significant modules identified the mitochondrion-mediated metabolic processes and pathways, and the cell cycle as the key biological processes and pathways in HCC. Subsequently, 28 hub genes were screened out by constructing protein-protein interaction network using Metascape. Finally, three genes (NDUFAF6, CKAP5, and DSN1 genes) were identified to be potential prognostic and key genes in HCC based on Kaplan-Meier survival analysis, GEO dataset validation, and literature review. Conclusions: The authors found that mitochondrion-mediated metabolic processes and the cell cycle were the key biological processes and pathways in HCC. NDUFAF6, CKAP5, and DSN1 genes were valuable genes with the potential to be prognosis biomarkers and targeted therapies in HCC.
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Affiliation(s)
- Huijie Lu
- Department of Anesthesiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Qianlin Zhu
- Department of Anesthesiology, Ruijin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China
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41
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Laneve P, Caffarelli E. The Non-coding Side of Medulloblastoma. Front Cell Dev Biol 2020; 8:275. [PMID: 32528946 PMCID: PMC7266940 DOI: 10.3389/fcell.2020.00275] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 03/31/2020] [Indexed: 12/18/2022] Open
Abstract
Medulloblastoma (MB) is the most common pediatric brain tumor and a primary cause of cancer-related death in children. Until a few years ago, only clinical and histological features were exploited for MB pathological classification and outcome prognosis. In the past decade, the advancement of high-throughput molecular analyses that integrate genetic, epigenetic, and expression data, together with the availability of increasing wealth of patient samples, revealed the existence of four molecularly distinct MB subgroups. Their further classification into 12 subtypes not only reduced the well-characterized intertumoral heterogeneity, but also provided new opportunities for the design of targets for precision oncology. Moreover, the identification of tumorigenic and self-renewing subpopulations of cancer stem cells in MB has increased our knowledge of its biology. Despite these advancements, the origin of MB is still debated, and its molecular bases are poorly characterized. A major goal in the field is to identify the key genes that drive tumor growth and the mechanisms through which they are able to promote tumorigenesis. So far, only protein-coding genes acting as oncogenic drivers have been characterized in each MB subgroup. The contribution of the non-coding side of the genome, which produces a plethora of transcripts that control fundamental biological processes, as the cell choice between proliferation and differentiation, is still unappreciated. This review wants to fill this major gap by summarizing the recent findings on the impact of non-coding RNAs in MB initiation and progression. Furthermore, their potential role as specific MB biomarkers and novel therapeutic targets is also highlighted.
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Affiliation(s)
- Pietro Laneve
- Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy
| | - Elisa Caffarelli
- Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy
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42
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Chen C, Guo Q, Song Y, Xu G, Liu L. SKA1/2/3 serves as a biomarker for poor prognosis in human lung adenocarcinoma. Transl Lung Cancer Res 2020; 9:218-231. [PMID: 32420061 PMCID: PMC7225159 DOI: 10.21037/tlcr.2020.01.20] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Background Spindle and kinetochore associated complex subunit 1/2/3 (SKA1/2/3), which stabilized spindle microtubules attaching to kinetochore (KT) in the middle stage of mitosis, were dysregulated, and closely related to prognosis in several malignant tumors. Nevertheless, the potential clinical value of SKA1/2/3, especially in terms of prognosis and development of NSCLC, had not been fully elucidated. Methods ONCOMINE, GEPIA, UALCAN, TCGA, STRING and other databases were used to analyze the expression of SKA1/2/3 in patients with lung adenocarcinoma (LUAD) and its clinical value, and to explore the possible regulatory mechanism of SKA in the occurrence and development of LUAD. Results In patients with LUAD, SKA1/2/3 mRNA expression level was significantly up-regulated, and AUC was 0.9558, 0.7034 and 0.9775, respectively. Increased SKA 1/2/3 expression was associated with smoking, tissue typing, and poor prognosis in LUAD patients. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) showed that SKA1/2/3 was mainly enriched in DNA replication, cell cycle, homologous recombination, p53 signaling pathway, etc. Hub genes in protein-protein interactions are CDK1, BUB1, CCNA2, CDC20, CCNB2, CCNB1, BUB1B, AURKB, TOP2A and MAD2L1. Hub gene expression in LUAD is increased, and its increased expression is related to poor prognosis of LUAD patients. Finally, the expression of SKA1/2/3 and its correlation with clinicopathological features were verified in 30 clinical LUAD samples. Conclusions SKA1/2/3 may serve as a potential prognostic biomarker and target for LUAD. In addition, SKA 1/2/3 may affect the prognosis of LUAD through DNA replication, cell cycle, homologous recombination and p53 signaling pathway.
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Affiliation(s)
- Cheng Chen
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu 610041, China.,Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Qiang Guo
- Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Yongxiang Song
- Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Gang Xu
- Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Lunxu Liu
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
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Zhou H, Yang Z, Yue J, Chen Y, Chen T, Mu T, Liu H, Bi X. Identification of potential hub genes via bioinformatics analysis combined with experimental verification in colorectal cancer. Mol Carcinog 2020; 59:425-438. [PMID: 32064687 DOI: 10.1002/mc.23165] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 01/23/2020] [Accepted: 01/31/2020] [Indexed: 12/18/2022]
Abstract
Colorectal cancer (CRC) is a kind of malignant cancer with high morbidity and mortality. The purpose of this study was to explore potential regulated key genes involved in CRC through bioinformatics analysis and experimental verification. The gene expression profile data were downloaded from the Gene Expression Omnibus, and the differential expression genes were detected in cancerous and paracancerous samples of CRC patients, respectively. Then functional enrichment analysis, such as the Kyoto Encyclopedia of Genes and Genomes pathway analysis as well as the protein-protein interaction network were constructed, and the highly related genes were clustered by Molecular COmplex DEtection algorithm to find out the core interaction in different genes' crosstalk. The genes affecting CRC prognosis were screened by the Human Protein Atlas database. In addition, the expression level of core genes was detected by GEPIA database, and the core genes' changes in large-scale cancer genome data set were directly analyzed by cBioPortal database. The expression of the predicted hub genes DSN1, AHCY, and ERCC6L was verified by reverse-transcription quantitative polymerase chain reaction in CRC cells. The gene function of DSN1 was analyzed by wound healing and colony formation assays. The results showed that silencing of DSN1 could significantly reduce the migration and proliferation of CRC cells. Further, BUB1B, the potential interacting protein of DSN1, was also predicted via bioinformatics analysis. Above all, this study shows that bioinformatics analysis combined with experimental method verification provide more potential vital genes for the prevention and therapy of CRC.
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Affiliation(s)
- Hongrui Zhou
- College of Life Science, Liaoning University, Shenyang, China
| | - Zhe Yang
- College of Life Science, Liaoning University, Shenyang, China
| | - Jiaxin Yue
- College of Life Science, Liaoning University, Shenyang, China
| | - Yang Chen
- College of Life Science, Liaoning University, Shenyang, China
| | - Tianqiao Chen
- College of Life Science, Liaoning University, Shenyang, China
| | - Teng Mu
- College of Life Science, Liaoning University, Shenyang, China
| | - Hongsheng Liu
- College of Life Science, Liaoning University, Shenyang, China
- Research Center for Computer Simulating and Information Processing of Bio-macromolecules of Liaoning Province, Liaoning University, Shenyang, China
| | - Xiuli Bi
- College of Life Science, Liaoning University, Shenyang, China
- Research Center for Computer Simulating and Information Processing of Bio-macromolecules of Liaoning Province, Liaoning University, Shenyang, China
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Hou Y, Wang Z, Huang S, Sun C, Zhao J, Shi J, Li Z, Wang Z, He X, Tam NL, Wu L. SKA3 Promotes tumor growth by regulating CDK2/P53 phosphorylation in hepatocellular carcinoma. Cell Death Dis 2019; 10:929. [PMID: 31804459 PMCID: PMC6895034 DOI: 10.1038/s41419-019-2163-3] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 11/20/2019] [Accepted: 11/21/2019] [Indexed: 01/20/2023]
Abstract
Spindle and kinetochore-related complex subunit 3 (SKA3) is a component of the spindle and kinetochore-related complexes and is essential for accurate timing of late mitosis. However, the relationship between SKA3 and hepatocellular carcinoma (HCC) has not yet been fully elucidated. Gene expression omnibus (GEO) (GSE62232, GSE45436, GSE6764, and GSE36376) and The Cancer Atlas (TCGA) datasets were analyzed to identify differential expression genes. Cell proliferation ability was analyzed using Cell Counting Kit-8 (CCK8) assay and plate clone formation assay, while scratch wound healing assay and transwell assay were used to analyze cell invasion. The role of SKA3 in vivo was explored using subcutaneous xenotransplantation model and lung metastasis model. Bioinformatics analysis found that hepatocellular carcinoma patients with high levels of expression of SKA3 have a poor prognosis. Similarly, immunohistochemical staining of 236 samples of tumors also found higher SKA3 expression in them, than in adjacent normal liver tissues. Significant levels of inhibition of in vivo and in vitro tumor proliferation and invasion result from the downregulation of SKA3. Mechanistically, SKA3 was found to affect tumor progression through the cell cycle and P53 signaling pathway as shown by the gene enrichment analysis (GSEA). G2/M phase arrest and severe apoptosis was also found to result from SKA3 knockdown, as shown by the inhibition of CDK2/p53 phosphorylation together with downregulation of BAX/Bcl-2 expression in HCC cells. Overall, these findings uncover the role of SKA3 in regulating the apoptosis and proliferation of hepatocellular carcinoma cells. This study was able to uncover new information on the tumorigenesis mechanism in hepatocellular carcinoma.
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Affiliation(s)
- Yuchen Hou
- Department of Organ Transplantation, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China.,Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China
| | - Ziming Wang
- Department of Biliary and Pancreatic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Shanzhou Huang
- Department of Organ Transplantation, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China.,Department of General Surgery, Guangdong Provincial People's Hospital. Guangdong Academy of Medical Sciences, Guangzhou, 510030, China
| | - Chengjun Sun
- Department of Organ Transplantation, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jingya Zhao
- The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
| | - Jiayu Shi
- The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
| | - Zhongqiu Li
- Department of Organ Transplantation, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Zekang Wang
- Department of Organ Transplantation, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xiaoshun He
- Department of Organ Transplantation, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China. .,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. .,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Nga Lei Tam
- Digestive Medical Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.
| | - Linwei Wu
- Department of Organ Transplantation, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China. .,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. .,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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Sun RL, Liu FJ, Wu X, Wang LS, Wang PF, Zhang CL. SKA3 Up-regulation Promotes Lung Adenocarcinoma Growth and is a Predictor of Poor Prognosis. Open Life Sci 2019; 14:392-399. [PMID: 33817174 PMCID: PMC7874813 DOI: 10.1515/biol-2019-0044] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 05/06/2019] [Indexed: 11/15/2022] Open
Abstract
Objective The objective of this research is to investigate the expression and function of SKA3 in lung adenocarcinoma. Methods The mRNA expression level of SKA3 in lung adenocarcinoma and its association with clinic-pathological factors were analyzed using data obtained from the TCGA database. Small interfering RNA (siRNA) for SKA3 (si-SKA3) was used to down-regulate SKA3 in A549 cells. pcDNA3.1- SKA3 was used to overexpress SKA3 in A549 cells. The proliferation ability of A549 cells was determined via MTT assay and colony formation assay. A wound healing assay was performed to examine the migration ability of A549 cells. The protein expression of p-MEK, MEK, p-ERK and ERK were determined by western blot. Results We found that SKA3 is up-regulated in lung adenocarcinoma compared to the normal lung tissues. Kaplan-Meier analysis showed that high SKA3 expression is markedly associated with poor prognosis in lung adenocarcinoma patients. SKA3 expression is significantly correlated with age, gender, pathologic-stage, pathologic-N and pathologic-M. Moreover, depleting SKA3 obviously inhibited A549 cell proliferation and migration in vitro, while overexpression of SKA3 notably increased A549 cell proliferation and migration. Western blot analysis showed that the protein expression ratio of p-MEK/MEK and p-ERK/ERK decreased noticeably after depleting SKA3. Conclusion SKA3 expression was enhanced and associated with poor prognosis in lung adenocarcinoma patients, and it might play a facilitating role in cell growth and motility by regulating the MAPK signaling pathway.
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Affiliation(s)
- Rong-Li Sun
- Department of Respiratory, The Affiliated Central Hospital of Qingdao University, No.127 Siliu South Road, Qingdao, Shandong 266042, P.R. China
| | - Feng-Juan Liu
- Department of Respiratory, The Affiliated Central Hospital of Qingdao University, No.127 Siliu South Road, Qingdao, Shandong 266042, P.R. China
| | - Xiao Wu
- Department of Respiratory, The Affiliated Central Hospital of Qingdao University, No.127 Siliu South Road, Qingdao, Shandong 266042, P.R. China
| | - Li-Sheng Wang
- Department of Respiratory, The Affiliated Central Hospital of Qingdao University, No.127 Siliu South Road, Qingdao, Shandong 266042, P.R. China
| | - Peng-Fei Wang
- Department of Respiratory, The Affiliated Central Hospital of Qingdao University, No.127 Siliu South Road, Qingdao, Shandong 266042, P.R. China
| | - Chun-Ling Zhang
- Department of Respiratory, The Affiliated Central Hospital of Qingdao University, No.127 Siliu South Road, Qingdao, Shandong 266042, P.R. China
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Chen J, Wang Z, Shen X, Cui X, Guo Y. Identification of novel biomarkers and small molecule drugs in human colorectal cancer by microarray and bioinformatics analysis. Mol Genet Genomic Med 2019; 7:e00713. [PMID: 31087508 PMCID: PMC6625111 DOI: 10.1002/mgg3.713] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 04/01/2019] [Accepted: 04/15/2019] [Indexed: 12/15/2022] Open
Abstract
Background Colorectal cancer (CRC) is one of the most common malignant tumors. In the present study, the expression profile of human multistage colorectal mucosa tissues, including healthy, adenoma, and adenocarcinoma samples was downloaded to identify critical genes and potential drugs in CRC. Methods Expression profiles, GSE33113 and GSE44076, were integrated using bioinformatics methods. Differentially expressed genes (DEGs) were analyzed by R language. Functional enrichment analyses of the DEGs were performed using the Database for Annotation, visualization, and integrated discovery (DAVID) database. Then, the search tool for the retrieval of interacting genes (STRING) database and Cytoscape were used to construct a protein–protein interaction (PPI) network and identify hub genes. Subsequently, survival analysis was performed among the key genes using Gene Expression Profiling Interactive Analysis (GEPIA). Connectivity Map (CMap) was used to query potential drugs for CRC. Results A total of 428 upregulated genes and 751 downregulated genes in CRC were identified. The functional changes of these DEGs were mainly associated with cell cycle, oocyte meiosis, DNA replication, p53 signaling pathway, and progesterone‐mediated oocyte maturation. A PPI network was identified by STRING with 482 nodes and 2,368 edges. Survival analysis revealed that high mRNA expression of AURKA, CCNB1, CCNF, and EXO1 was significantly associated with longer overall survival. Moreover, CMap predicted a panel of small molecules as possible adjuvant drugs to treat CRC. Conclusion Our study found key dysregulated genes involved in CRC and potential drugs to combat it, which may provide novel insights and potential biomarkers for prognosis, as well as providing new CRC treatments.
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Affiliation(s)
- Juan Chen
- Laboratory Medicine Center, People's Hospital of Hai'an County, Nantong, P. R. China
| | - Ziheng Wang
- Department of Clinical Biobank, Nantong University Affiliated Hospital, Nantong, P. R. China.,Department of Medicine, Nantong University Xinling college, Nantong, P.R. China
| | - Xianjuan Shen
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, P. R. China
| | - Xiaopeng Cui
- Department of general surgery, Affiliated Hospital of Nantong University, Nantong, P. R. China
| | - Yuehua Guo
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, P. R. China
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Lu J, Zhang P, Xie J, Wang J, Lin J, Chen Q, Cao L, Huang C, Li P, Zheng C. Hsa_circ_0000467 promotes cancer progression and serves as a diagnostic and prognostic biomarker for gastric cancer. J Clin Lab Anal 2019; 33:e22726. [PMID: 30461077 PMCID: PMC6818566 DOI: 10.1002/jcla.22726] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 10/30/2018] [Accepted: 10/30/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Emerging evidence indicates that dysregulation of circular RNAs (circRNAs) is implicated in the development of malignancies. However, the diagnostic value and functional role of circRNAs in gastric cancer (GC) remain largely elusive. METHODS Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to detect the expression of hsa_circ_0000467 in tissues, cell lines, and plasma. A receiver operating characteristic (ROC) curve was constructed to estimate the diagnostic value of hsa_circ_0000467. The association between the expression level of hsa_circ_0000467 and the clinicopathological features was analyzed. Moreover, cell functional assays were performed. RESULTS Hsa_circ_0000467 was significantly upregulated in GC tissue compared to adjacent nontumor tissue (n = 51, P < 0.05). Similar results were detected in the HGC-27, MGC-803, AGS, NUGC-3, GES-1 cell lines (n = 15, P < 0.001), and in the plasma samples from GC patients (n = 20, P < 0.05). The area under the ROC curve of hsa_circ_0000467 was 0.790, which is superior to commonly used biomarkers including CEA and CA-724. We found that the expression levels of hsa_circ_0000467 in the same patient were significantly lower after surgery (n = 20, P < 0.05). Moreover, the hsa_circ_0000467 expression level is closely associated with TNM stage. Additionally, Cox multivariate analysis showed that hsa_circ_0000467 is a novel independent prognostic factor. Furthermore, in vitro experiments demonstrated that knockdown of hsa_circ_0000467 markedly inhibited the proliferation, migration, and invasion of GC cells. Moreover, hsa_circ_0000467 silencing increased tumor apoptosis in vitro. CONCLUSION Hsa_circ_0000467 can act as a novel noninvasive biomarker for the diagnosis and prognosis of GC and may be a potential therapeutic target for GC.
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Affiliation(s)
- Jun Lu
- Department of Gastric SurgeryFujian Medical University Union HospitalFuzhouChina
- Department of General SurgeryFujian Medical University Union HospitalFuzhouChina
- Key Laboratory of Ministry of Education of Gastrointestinal CancerFujian Medical UniversityFuzhouChina
| | - Peng‐yang Zhang
- Department of Gastric SurgeryFujian Medical University Union HospitalFuzhouChina
- Department of General SurgeryFujian Medical University Union HospitalFuzhouChina
- Key Laboratory of Ministry of Education of Gastrointestinal CancerFujian Medical UniversityFuzhouChina
| | - Jian‐wei Xie
- Department of Gastric SurgeryFujian Medical University Union HospitalFuzhouChina
- Department of General SurgeryFujian Medical University Union HospitalFuzhouChina
- Key Laboratory of Ministry of Education of Gastrointestinal CancerFujian Medical UniversityFuzhouChina
| | - Jia‐bin Wang
- Department of Gastric SurgeryFujian Medical University Union HospitalFuzhouChina
- Department of General SurgeryFujian Medical University Union HospitalFuzhouChina
- Key Laboratory of Ministry of Education of Gastrointestinal CancerFujian Medical UniversityFuzhouChina
| | - Jian‐xian Lin
- Department of Gastric SurgeryFujian Medical University Union HospitalFuzhouChina
- Department of General SurgeryFujian Medical University Union HospitalFuzhouChina
- Key Laboratory of Ministry of Education of Gastrointestinal CancerFujian Medical UniversityFuzhouChina
| | - Qi‐yue Chen
- Department of Gastric SurgeryFujian Medical University Union HospitalFuzhouChina
- Department of General SurgeryFujian Medical University Union HospitalFuzhouChina
- Key Laboratory of Ministry of Education of Gastrointestinal CancerFujian Medical UniversityFuzhouChina
| | - Long‐long Cao
- Department of Gastric SurgeryFujian Medical University Union HospitalFuzhouChina
- Department of General SurgeryFujian Medical University Union HospitalFuzhouChina
- Key Laboratory of Ministry of Education of Gastrointestinal CancerFujian Medical UniversityFuzhouChina
| | - Chang‐ming Huang
- Department of Gastric SurgeryFujian Medical University Union HospitalFuzhouChina
- Department of General SurgeryFujian Medical University Union HospitalFuzhouChina
- Key Laboratory of Ministry of Education of Gastrointestinal CancerFujian Medical UniversityFuzhouChina
| | - Ping Li
- Department of Gastric SurgeryFujian Medical University Union HospitalFuzhouChina
- Department of General SurgeryFujian Medical University Union HospitalFuzhouChina
- Key Laboratory of Ministry of Education of Gastrointestinal CancerFujian Medical UniversityFuzhouChina
| | - Chao‐hui Zheng
- Department of Gastric SurgeryFujian Medical University Union HospitalFuzhouChina
- Department of General SurgeryFujian Medical University Union HospitalFuzhouChina
- Key Laboratory of Ministry of Education of Gastrointestinal CancerFujian Medical UniversityFuzhouChina
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48
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Huang CH, Chen CJ, Chen PN, Wang SS, Chou YE, Hung SC, Yang SF. Impacts of AURKA Genetic Polymorphism on Urothelial Cell Carcinoma Development. J Cancer 2019; 10:1370-1374. [PMID: 31031846 PMCID: PMC6485228 DOI: 10.7150/jca.30014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 01/16/2019] [Indexed: 12/14/2022] Open
Abstract
Urothelial cell carcinoma (UCC) is the most common primary malignancy of the urinary system and the second-most common type of renal cell carcinoma. Aurora kinase A (AURKA), a serine/threonine kinase, has a critical role in centrosome duplication, spindle assembly checkpoint, and cytokinesis. Here, we determined the correlation between UCC susceptibility and AURKA polymorphisms. We used real-time polymerase chain reaction to compare the genotype distributions and allelic frequencies of four single-nucleotide polymorphisms (SNPs) of AURKA, namely rs1047972, rs2273535, rs2064863, and rs6024836, between 431 UCC cases and 862 healthy controls. Logistic regression models demonstrated that the G allele of rs2064863, a genetic polymorphism of AURKA, exhibited a significant protective effect against UCC among the 862 nonsmokers. Moreover, patients with rs2064863 G allele exhibited a slightly lower risk of lymph node metastasis and those with rs6024836 G allele exhibited a lower risk of distant metastases. Our study suggested that several variants of AURKA SNPs rs2064863 and rs6024836 may serve as critical predictors for the clinical status of UCC.
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Affiliation(s)
- Chia-Hung Huang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Division of Nephrology, Department of Internal Medicine, Lin Shin Hospital, Taichung, Taiwan
| | - Chih-Jung Chen
- Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Pei-Ni Chen
- Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan
| | - Shian-Shiang Wang
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Ying-Erh Chou
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Sheng-Chun Hung
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
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49
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Guo M, Lu S, Huang H, Wang Y, Yang MQ, Yang Y, Fan Z, Jiang B, Deng Y. Increased AURKA promotes cell proliferation and predicts poor prognosis in bladder cancer. BMC SYSTEMS BIOLOGY 2018; 12:118. [PMID: 30547784 PMCID: PMC6293497 DOI: 10.1186/s12918-018-0634-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Background Bladder cancer (BC) is the most common cancer of the urinary bladder and upper tract, in which the clinical management is limited. AURKA (aurora kinase A) has been identified as an oncogene in cancer development; however, its potential role and underlying mechanisms in the progression of BC remain unknown. Results In this study, we evaluated Aurora kinase A (AURKA) expression in patient samples by performing gene expression profiling, and found that AURKA expression levels were significantly higher in BC tissues than in normal tissues. Increased AURKA in BC was strongly associated with stage and grade. Moreover, BC patients with elevated AURKA achieved poor overall survival rates. The experiments in vitro comprehensively validated the critical role of AURKA in promoting BC cell proliferation using the methods of gene overexpression and gene silencing. Furthermore, we proved that AURKA inhibitor MLN8237 arrested BC cell growth and induced apoptosis. Conclusions These findings implicate AURKA acting as an effective biomarker for BC detection and prognosis, as well as therapeutic target.
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Affiliation(s)
- Mengjie Guo
- School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Sicheng Lu
- School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Hongming Huang
- Department of Hematology, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Yaohui Wang
- Department of Pathology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, 210029, China
| | - Mary Q Yang
- MidSouth Bioinformatics Center, Department of Information Science, George Washington Donaghey College of Engineering and Information Technology and Joint Bioinformatics Graduate Program, University of Arkansas at Little Rock and University of Arkansas for Medical Sciences, Little Rock, AR, 72204, USA
| | - Ye Yang
- National Medical Centre of Colorectal Disease, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210001, China.,Integrated Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Zhimin Fan
- National Medical Centre of Colorectal Disease, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210001, China.
| | - Bin Jiang
- National Medical Centre of Colorectal Disease, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210001, China.
| | - Youping Deng
- National Medical Centre of Colorectal Disease, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210001, China. .,Bioinformatics Core, Department of Complementary & Integrative Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, HI, 96813, USA.
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50
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Hu R, Wang MQ, Niu WB, Wang YJ, Liu YY, Liu LY, Wang M, Zhong J, You HY, Wu XH, Deng N, Lu L, Wei LB. SKA3 promotes cell proliferation and migration in cervical cancer by activating the PI3K/Akt signaling pathway. Cancer Cell Int 2018; 18:183. [PMID: 30459531 PMCID: PMC6236911 DOI: 10.1186/s12935-018-0670-4] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 10/30/2018] [Indexed: 01/03/2023] Open
Abstract
Background Cervical cancer (CC) is one of the most common cancers among females worldwide. Spindle and kinetochore-associated complex subunit 3 (SKA3), located on chromosome 13q, was identified as a novel gene involved in promoting malignant transformation in cancers. However, the function and underlying mechanisms of SKA3 in CC remain unknown. Using the Oncomine database, we found that expression of SKA3 mRNA is higher in CC tissues than in normal tissues and is linked with poor prognosis. Methods In our study, immunohistochemistry showed increased expression of SKA3 in CC tissues. The effect of SKA3 on cell proliferation and migration was evaluated by CCK8, clone formation, Transwell and wound-healing assays in HeLa and SiHa cells with stable SKA3 overexpression and knockdown. In addition, we established a xenograft tumor model in vivo. Results SKA3 overexpression promoted cell proliferation and migration and accelerated tumor growth. We further identified that SKA3 is involved in regulating cell cycle progression and the PI3K/Akt signaling pathway via RNA-sequencing (RNA-Seq) and gene set enrichment analyses. Western blotting results revealed that SKA3 overexpression increased levels of p-Akt, cyclin E2, CDK2, cyclin D1, CDK4, E2F1 and p-Rb in HeLa cells. Additionally, the use of an Akt inhibitor (GSK690693) significantly reversed the cell proliferation capacity induced by SKA3 overexpression in HeLa cells. Conclusions We suggest that SKA3 overexpression contributes to CC cell growth and migration by promoting cell cycle progression and activating the PI3K-Akt signaling pathway, which may provide potential novel therapeutic targets for CC treatment.
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Affiliation(s)
- Rong Hu
- 1Shenzhen Hospital, Southern Medical University, No. 1333, Xinhu Road, Bao'an District, Shenzhen, 518101 Guangdong China.,2School of Traditional Chinese Medicine, Southern Medical University, No. 1838, Guangzhou Avenue North, Baiyun District, Guangzhou, 510515 Guangdong China
| | - Ming-Qing Wang
- 1Shenzhen Hospital, Southern Medical University, No. 1333, Xinhu Road, Bao'an District, Shenzhen, 518101 Guangdong China.,2School of Traditional Chinese Medicine, Southern Medical University, No. 1838, Guangzhou Avenue North, Baiyun District, Guangzhou, 510515 Guangdong China
| | - Wen-Bo Niu
- 5Cancer Research Institute, Southern Medical University, No. 1838, Guangzhou Avenue North, Baiyun District, Guangzhou, 510515 Guangdong China
| | - Yan-Jing Wang
- 3Zhujiang Hospital of Southern Medical University, No. 253, Industrial Avenue, Haizhu District, Guangzhou, 510280 Guangdong China
| | - Yang-Yang Liu
- Zhongshan Huangpu People's Hospital, No. 32, Long'an Street, Huangpu Town, Zhongshan, 528429 Guangdong China
| | - Ling-Yu Liu
- 1Shenzhen Hospital, Southern Medical University, No. 1333, Xinhu Road, Bao'an District, Shenzhen, 518101 Guangdong China.,2School of Traditional Chinese Medicine, Southern Medical University, No. 1838, Guangzhou Avenue North, Baiyun District, Guangzhou, 510515 Guangdong China
| | - Ming Wang
- 3Zhujiang Hospital of Southern Medical University, No. 253, Industrial Avenue, Haizhu District, Guangzhou, 510280 Guangdong China
| | - Juan Zhong
- 1Shenzhen Hospital, Southern Medical University, No. 1333, Xinhu Road, Bao'an District, Shenzhen, 518101 Guangdong China.,2School of Traditional Chinese Medicine, Southern Medical University, No. 1838, Guangzhou Avenue North, Baiyun District, Guangzhou, 510515 Guangdong China
| | - Hai-Yan You
- 1Shenzhen Hospital, Southern Medical University, No. 1333, Xinhu Road, Bao'an District, Shenzhen, 518101 Guangdong China.,2School of Traditional Chinese Medicine, Southern Medical University, No. 1838, Guangzhou Avenue North, Baiyun District, Guangzhou, 510515 Guangdong China
| | - Xiao-Hui Wu
- 1Shenzhen Hospital, Southern Medical University, No. 1333, Xinhu Road, Bao'an District, Shenzhen, 518101 Guangdong China.,2School of Traditional Chinese Medicine, Southern Medical University, No. 1838, Guangzhou Avenue North, Baiyun District, Guangzhou, 510515 Guangdong China
| | - Ning Deng
- 2School of Traditional Chinese Medicine, Southern Medical University, No. 1838, Guangzhou Avenue North, Baiyun District, Guangzhou, 510515 Guangdong China
| | - Lu Lu
- 4The First Affiliated Hospital, Guangzhou University of Chinese Medicine, No.16 Baiyun Airport Road, Baiyun District, Guangzhou, 510405 Guangdong China
| | - Lian-Bo Wei
- 1Shenzhen Hospital, Southern Medical University, No. 1333, Xinhu Road, Bao'an District, Shenzhen, 518101 Guangdong China.,2School of Traditional Chinese Medicine, Southern Medical University, No. 1838, Guangzhou Avenue North, Baiyun District, Guangzhou, 510515 Guangdong China
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